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Novel Functions of the Septin Cytoskeleton

Shaping Up Tissue Inflammation and Fibrosis
  • Andrei I. Ivanov
    Correspondence
    Address correspondence to Andrei I. Ivanov, Ph.D. or Florian Rieder, M.D., Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NC22, Cleveland, OH 44195.
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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  • Hongnga T. Le
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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  • Nayden G. Naydenov
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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  • Florian Rieder
    Correspondence
    Address correspondence to Andrei I. Ivanov, Ph.D. or Florian Rieder, M.D., Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NC22, Cleveland, OH 44195.
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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Open ArchivePublished:October 07, 2020DOI:https://doi.org/10.1016/j.ajpath.2020.09.007
      Chronic inflammatory diseases cause profound alterations in tissue homeostasis, including unchecked activation of immune and nonimmune cells leading to disease complications such as aberrant tissue repair and fibrosis. Current anti-inflammatory therapies are often insufficient in preventing or reversing these complications. Remodeling of the intracellular cytoskeleton is critical for cell activation in inflamed and fibrotic tissues; however, the cytoskeleton has not been adequately explored as a therapeutic target in inflammation. Septins are GTP-binding proteins that self-assemble into higher order cytoskeletal structures. The septin cytoskeleton exhibits a number of critical cellular functions, including regulation of cell shape and polarity, cytokinesis, cell migration, vesicle trafficking, and receptor signaling. Surprisingly, little is known about the role of the septin cytoskeleton in inflammation. This article reviews emerging evidence implicating different septins in the regulation of host-pathogen interactions, immune cell functions, and tissue fibrosis. Targeting of the septin cytoskeleton as a potential future therapeutic intervention in human inflammatory and fibrotic diseases is also discussed.
      Acute and chronic inflammation result in dramatic changes in tissue homeostasis. These changes include altered cellular composition and interactions between immune and nonimmune cells in affected tissues, as well as the perturbed biochemical environment driven by the release of various pro- and anti-inflammatory mediators.
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      Activation of resolution pathways to prevent and fight chronic inflammation: lessons from asthma and inflammatory bowel disease.
      ,
      • Brazil J.C.
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      Innate immune cell-epithelial crosstalk during wound repair.
      Similarly, the physical properties of affected tissues change due to acute and chronic inflammation-induced development of edema, aberrant tissue remodeling, and fibrosis.
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      Pathogenesis of fibrostenosing Crohn's disease.
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      Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues: a scoping review.
      On a cellular level, inflammatory states result in functional adaptations toward accelerated recognition and elimination of the invaded pathogens, as well as enhanced production of extracellular matrix and tissue turnover.
      • Brazil J.C.
      • Quiros M.
      • Nusrat A.
      • Parkos C.A.
      Innate immune cell-epithelial crosstalk during wound repair.
      ,
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      Molecular pathways driving disease-specific alterations of intestinal epithelial cells.
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      • Manon-Jensen T.
      The intestinal tissue homeostasis - the role of extracellular matrix remodeling in inflammatory bowel disease.
      These alterations of cellular function in inflamed tissues are mediated by reprograming of the fundamental molecular processes, including gene expression, protein synthesis, vesicle trafficking, and cytoskeletal assembly.
      The cytoskeleton is a critical regulator of the architecture and function of eukaryotic cells. It comprises various filamentous structures formed via self-assembly and the polymerization of specialized proteins.
      • Hohmann T.
      • Dehghani F.
      The cytoskeleton-a complex interacting meshwork.
      The four components of the cytoskeleton include: actin filaments, microtubules, intermediate filaments, and septin polymers. These cytoskeletal elements play crucial roles in mediating housekeeping and specialized functions in multiple cell types. Examples include regulation of cell shape and size, cell division, migration, cell–cell interactions, protein uptake and secretion, receptor signaling, etc.
      • Hohmann T.
      • Dehghani F.
      The cytoskeleton-a complex interacting meshwork.
      • Mostowy S.
      • Cossart P.
      Septins: the fourth component of the cytoskeleton.
      • Tang D.D.
      • Gerlach B.D.
      The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration.
      Defects in the assembly and remodeling of different cytoskeletal elements play major roles in the development of various diseases, which is exemplified by tumor progression and metastasis.
      • Hohmann T.
      • Dehghani F.
      The cytoskeleton-a complex interacting meshwork.
      ,
      • Angelis D.
      • Spiliotis E.T.
      Septin mutations in human cancers.
      ,
      • Fife C.M.
      • McCarroll J.A.
      • Kavallaris M.
      Movers and shakers: cell cytoskeleton in cancer metastasis.
      The cytoskeletal regulation of tissue inflammation has also been extensively investigated. For example, the actin cytoskeleton controls the inflammatory response by regulating activation of immune cells and permeability of epithelial and endothelial barriers.
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      • Carisey A.
      • Oszmiana A.
      • Kennedy P.R.
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      • Davis D.M.
      The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse.
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      Disruption of the epithelial barrier during intestinal inflammation: quest for new molecules and mechanisms.
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      • Rossaint J.
      • Zarbock A.
      Actin dynamics in the regulation of endothelial barrier functions and neutrophil recruitment during endotoxemia and sepsis.
      Microtubules regulate pathogens sensing by inflammasomes,
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      The pyrin inflammasome in host-microbe interactions.
      assembly of the immune synapse,
      • Martin-Cofreces N.B.
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      • Sanchez-Madrid F.
      Immune synapse: conductor of orchestrated organelle movement.
      and vascular leakage in the inflamed tissues.
      • Karki P.
      • Birukova A.A.
      Microtubules-associated Rac regulation of endothelial barrier: a role of Asef in acute lung injury.
      Finally, intermediate filaments have been implicated in glial cell activation during neural inflammation
      • Pekny M.
      • Wilhelmsson U.
      • Bogestal Y.R.
      • Pekna M.
      The role of astrocytes and complement system in neural plasticity.
      and development of inflammatory skin disorders.
      • Coulombe P.A.
      • Kerns M.L.
      • Fuchs E.
      Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility.
      Although the roles of actin filaments, microtubules, and intermediate filament in tissue inflammation has attracted significant attention, the role of the fourth cytoskeletal element, the septin cytoskeleton, in modulating the inflammatory response remains poorly understood. This review addresses this knowledge gap by summarizing existing evidence for the involvement of the septin cytoskeleton in inflammation and tissue fibrosis and outlining possible mechanisms of such involvement.

      Diversity of the Septin Protein Family

      Septins (SEPT) are small GTP-binding proteins abundantly expressed in all eukaryotic organisms except for higher plants. In mammals, there are 13 septin genes (SEPT1 to SEPT12 and SEPT14) and at least 11 pseudogenes, with extensive post-transcriptional alternative splicing in many septin genes.
      • Kinoshita M.
      Assembly of mammalian septins.
      ,
      • Russell S.E.
      • Hall P.A.
      Septin genomics: a road less travelled.
      Existence of multiple members of the septin family (paralogs) along with expression of their differentially spliced isoforms gives rise to a complex array of different septin proteins playing either redundant or unique functional roles in different tissues. Bioinformatics analysis of the amino acid sequence homology separates mammalian septins into the following four groups named by their founding members: SEPT2 (SEPT1, -2, -4, and -5), SEPT3 (SEPT3, -9, and -12), SEPT6 (SEPT6, -8, -10, -11, and -14), and SEPT7 (SEPT7).
      • Kinoshita M.
      Assembly of mammalian septins.
      All members of these groups share a GTP-binding domain flanked by an N-terminal polybasic domain and a C-terminal septin unique element.
      • Valadares N.F.
      • d' Muniz Pereira H.
      • Ulian Araujo A.P.
      • Garratt R.C.
      Septin structure and filament assembly.
      The groups diverge in their N-terminal extensions and C-terminal parts that contain different number of coiled-coil repeats.
      Although septins are widely expressed in human tissues, some septin paralogs (SEPT2, -4, -7, -8, -9, and -10) appear to be ubiquitous, whereas others are enriched in specific tissues.
      • Hall P.A.
      • Jung K.
      • Hillan K.J.
      • Russell S.E.
      Expression profiling the human septin gene family.
      ,
      • Zuvanov L.
      • Mota D.M.D.
      • Araujo A.P.U.
      • DeMarco R.
      A blueprint of septin expression in human tissues.
      For example, high expression of SEPT3, -4, -5, and -8 is observed in the central nervous system, SEPT1, -6, and -9 are enriched in hematopoietic cells, whereas SEPT12 is especially abundant in testes.
      • Hall P.A.
      • Jung K.
      • Hillan K.J.
      • Russell S.E.
      Expression profiling the human septin gene family.
      ,
      • Zuvanov L.
      • Mota D.M.D.
      • Araujo A.P.U.
      • DeMarco R.
      A blueprint of septin expression in human tissues.
      A recent correlative analysis indicated consistent co-expression of subsets of septin paralogs in various tissues. For example, SEPT3 and SEPT5 expression displays high correlation in different brain regions, whereas a subset of septins including SEPT2, -7, -10, and to a lesser extent, SEPT11, are consistently co-expressed in non-neural tissues.
      • Zuvanov L.
      • Mota D.M.D.
      • Araujo A.P.U.
      • DeMarco R.
      A blueprint of septin expression in human tissues.
      It has been suggested that septin family members with highly correlated tissue expression could be parts of the same protein complexes.

      Assembly and Interactions of Septin Proteins

      One of the most characteristic features of septins is their ability to self-associate, forming nonpolar rod-like hetero-oligomers and higher-order polymeric structures. Although the existence of septin rod complexes is well-documented from yeasts to mammals, their exact molecular composition is a subject of continuous debates and revisions.
      • McMurray M.A.
      • Thorner J.
      Turning it inside out: the organization of human septin heterooligomers.
      Thus, recent studies have challenged a decade-old model of the organization of mammalian septin oligomers by suggesting a novel subunit arrangement in the rod complexes. According to these studies, the simplest building block of the septin cytoskeleton is composed of either six or eight protein subunits. A typical hexamer and octamer have the following subunit order: SEPT2-SEPT6-SEPT7-SEPT7-SEPT6-SEPT2 and SEPT2-SEPT6-SEPT7-SEPT9-SEPT-9-SEPT7-SEPT6-SEPT2, respectively.
      • McMurray M.A.
      • Thorner J.
      Turning it inside out: the organization of human septin heterooligomers.
      ,
      • Mendonca D.C.
      • Macedo J.N.
      • Guimaraes S.L.
      • Barroso da Silva F.L.
      • Cassago A.
      • Garratt R.C.
      • Portugal R.V.
      • Araujo A.P.U.
      A revised order of subunits in mammalian septin complexes.
      Such oligomeric composition suggests that members of all four septin groups participate in the complex formation. Furthermore, according to the Kinoshita rule, members of the same septin group are interchangeable in the oligomers. For example, SEPT2 may be replaced by either SEPT4 or SEPT5, whereas SEPT9 may be replaced by either SEPT3 or SEPT12. This enables the assembly of functional septin complexes in different tissues that express distinct repertoires of septin genes. Based on this, SEPT7, the only member in its group, is predicted to be the most common and important component of the septin cytoskeleton. Indeed, several studies have demonstrated that loss of SEPT7 destabilizes other subunits of the septin oligomers and triggers their degradation.
      • Menon M.B.
      • Sawada A.
      • Chaturvedi A.
      • Mishra P.
      • Schuster-Gossler K.
      • Galla M.
      • Schambach A.
      • Gossler A.
      • Forster R.
      • Heuser M.
      • Kotlyarov A.
      • Kinoshita M.
      • Gaestel M.
      Genetic deletion of SEPT7 reveals a cell type-specific role of septins in microtubule destabilization for the completion of cytokinesis.
      ,
      • Sun L.
      • Cao X.
      • Lechuga S.
      • Feygin A.
      • Naydenov N.G.
      • Ivanov A.I.
      A septin cytoskeleton-targeting small molecule, forchlorfenuron, inhibits epithelial migration via septin-independent perturbation of cellular signaling.
      The septin rod oligomers spontaneously collide to form short filaments that can further assemble by end-to-end joining or lateral interactions into bundles, rings, gauzes, and sheer-like structures (Figure 1).
      • Mostowy S.
      • Cossart P.
      Septins: the fourth component of the cytoskeleton.
      ,
      • Bridges A.A.
      • Gladfelter A.S.
      Septin form and function at the cell cortex.
      It is noteworthy that the composition of septin oligomers is primarily based on the in vitro reconstitution studies that utilized purified recombinant septin proteins.
      • McMurray M.A.
      • Thorner J.
      Turning it inside out: the organization of human septin heterooligomers.
      ,
      • Mendonca D.C.
      • Macedo J.N.
      • Guimaraes S.L.
      • Barroso da Silva F.L.
      • Cassago A.
      • Garratt R.C.
      • Portugal R.V.
      • Araujo A.P.U.
      A revised order of subunits in mammalian septin complexes.
      The composition of such oligomers could be much more complex in vivo. Septin complexes isolated from different mammalian cells belong to either the canonical hetero-oligomers (SEPT2, -6, -7, -9; SEPT3, -5, -7; or SEPT7, -9, -11), or have unusual subunit composition inconsistent with the canonical oligomerization (SEPT2, -5, -6, -7; SEPT4, -5, -8; SEPT2, -5, etc).
      • Dolat L.
      • Hu Q.
      • Spiliotis E.T.
      Septin functions in organ system physiology and pathology.
      It is also possible that the hetero-oligomerization is not an obligate mechanism of septin assembly and activity, and some septin family members can function as monomers or homo-oligomers. For example, loss of SEPT1, but not SEPT2, SEPT6, SEPT7, or SEPT9, has been shown to disrupt Golgi morphology in cervical cancer cells,
      • Song K.
      • Gras C.
      • Capin G.
      • Gimber N.
      • Lehmann M.
      • Mohd S.
      • Puchkov D.
      • Rödiger M.
      • Wilhelmi I.
      • Daumke O.
      • Schmoranzer J.
      • Schürmann A.
      • Krauss M.
      A SEPT1-based scaffold is required for Golgi integrity and function.
      which selectively implicates SEPT1 in the regulation of Golgi integrity and trafficking. Furthermore, a specific SEPT4 splice isoform, SEPT4_i2, alias apoptosis-related protein in the transforming growth factor (TGF)-β signaling pathway (ARTS), was shown to selectively localize to mitochondria in kidney epithelial cells and regulate cell apoptosis.
      • Larisch S.
      • Yi Y.
      • Lotan R.
      • Kerner H.
      • Eimerl S.
      • Tony Parks W.
      • Gottfried Y.
      • Birkey Reffey S.
      • de Caestecker M.P.
      • Danielpour D.
      • Book-Melamed N.
      • Timberg R.
      • Duckett C.S.
      • Lechleider R.J.
      • Steller H.
      • Orly J.
      • Kim S.J.
      • Roberts A.B.
      A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.
      Such peculiar functional activity of SEPT4 may be linked to its ability to homo-oligomerize and form amyloid-like filaments in vitro.
      • Garcia W.
      • de Araújo A.P.
      • Lara F.
      • Foguel D.
      • Tanaka M.
      • Tanaka T.
      • Garratt R.C.
      An intermediate structure in the thermal unfolding of the GTPase domain of human septin 4 (SEPT4/bradeion-beta) forms amyloid-like filaments in vitro.
      The unique cellular activities of certain septin paralogs and splice isoforms could add another level of complexity to the septin functions and regulation in different mammalian cells and tissues.
      Figure thumbnail gr1
      Figure 1Organization and cellular function of the septin cytoskeleton. The assembly of the septin cytoskeleton involves initial formation of hetero-oligomers with their subsequent polymerization into higher order structures. The most well-characterized functions of septin polymers include the regulation of cell division, migration, cell–cell adhesions, and intracellular vesicle trafficking.
      Importantly, a current paradigm considers the septin cytoskeleton as a universal molecular scaffold mediating the organization of other key cytoskeletal elements and their interactions with lipid membranes.
      • Mostowy S.
      • Cossart P.
      Septins: the fourth component of the cytoskeleton.
      ,
      • Bridges A.A.
      • Gladfelter A.S.
      Septin form and function at the cell cortex.
      ,
      • Dolat L.
      • Hu Q.
      • Spiliotis E.T.
      Septin functions in organ system physiology and pathology.
      This puts the septin cytoskeleton into the center of cytoskeletal regulation. Several important molecular features of septin polymers enable such a scaffolding role. First, due to a slow rate of the GTP hydrolysis, septin filaments are more stable compared with actin filaments and microtubules.
      • Hagiwara A.
      • Tanaka Y.
      • Hikawa R.
      • Morone N.
      • Kusumi A.
      • Kimura H.
      • Kinoshita M.
      Submembranous septins as relatively stable components of actin-based membrane skeleton.
      Hence, they can serve as templates and provide a structural memory for the assembly of more labile cytoskeletal elements. Second, septins are known to physically interact with and regulate the organization of actin filaments and microtubules.
      • Lam M.
      • Calvo F.
      Regulation of mechanotransduction: emerging roles for septins.
      ,
      • Spiliotis E.T.
      Spatial effects - site-specific regulation of actin and microtubule organization by septin GTPases.
      Indeed, Drosophila SEPT1/SEPT2/SEPT7 and human SEPT2/SEPT6/SEPT7 complexes, as well as human SEPT9 cross-link actin filaments into long, curved bundles.
      • Dolat L.
      • Hunyara J.L.
      • Bowen J.R.
      • Karasmanis E.P.
      • Elgawly M.
      • Galkin V.E.
      • Spiliotis E.T.
      Septins promote stress fiber-mediated maturation of focal adhesions and renal epithelial motility.
      ,
      • Mavrakis M.
      • Azou-Gros Y.
      • Tsai F.-C.
      • Alvarado J.
      • Bertin A.
      • Iv F.
      • Kress A.
      • Brasselet S.
      • Koenderink G.H.
      • Lecuit T.
      Septins promote F-actin ring formation by crosslinking actin filaments into curved bundles.
      Furthermore, SEPT9 suppresses F-actin disassembly caused by the actin-depolymerizing protein cofilin.
      • Smith C.
      • Dolat L.
      • Angelis D.
      • Forgacs E.
      • Spiliotis E.T.
      • Galkin V.E.
      Septin 9 exhibits polymorphic binding to f-actin and inhibits myosin and cofilin activity.
      SEPT2 and SEPT9 are known to interact with a key actin motor, nonmuscle myosin II (NM II).
      • Hecht M.
      • Rosler R.
      • Wiese S.
      • Johnsson N.
      • Gronemeyer T.
      An interaction network of the human SEPT9 established by quantitative mass spectrometry.
      ,
      • Joo E.
      • Surka M.C.
      • Trimble W.S.
      Mammalian SEPT2 is required for scaffolding nonmuscle myosin II and its kinases.
      Interestingly, such interactions have opposite effects on the NM II activity, with SEPT2 activating and SEPT9 inhibiting this motor protein.
      • Smith C.
      • Dolat L.
      • Angelis D.
      • Forgacs E.
      • Spiliotis E.T.
      • Galkin V.E.
      Septin 9 exhibits polymorphic binding to f-actin and inhibits myosin and cofilin activity.
      ,
      • Joo E.
      • Surka M.C.
      • Trimble W.S.
      Mammalian SEPT2 is required for scaffolding nonmuscle myosin II and its kinases.
      In addition to their association with actomyosin structures, septins also interact with microtubules.
      • Spiliotis E.T.
      Spatial effects - site-specific regulation of actin and microtubule organization by septin GTPases.
      SEPT9_i1 splice isoform directly binds to β-tubulin and induces microtubule bundling,
      • Bai X.
      • Bowen J.R.
      • Knox T.K.
      • Zhou K.
      • Pendziwiat M.
      • Kuhlenbaumer G.
      • Sindelar C.V.
      • Spiliotis E.T.
      Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules.
      whereas the SEPT2/6/7 complex preferentially associates with microtubule plus ends and modulates their dynamics.
      • Nakos K.
      • Radler M.R.
      • Spiliotis E.T.
      Septin 2/6/7 complexes tune microtubule plus-end growth and EB1 binding in a concentration- and filament-dependent manner.
      The functional relevance of these septin-microtubule interactions was highlighted by the findings that either SEPT2, or SEPT7 depletion disrupts different microtubule populations in polarized and migrating epithelial cells.
      • Bowen J.R.
      • Hwang D.
      • Bai X.
      • Roy D.
      • Spiliotis E.T.
      Septin GTPases spatially guide microtubule organization and plus end dynamics in polarizing epithelia.
      ,
      • Shindo A.
      • Audrey A.
      • Takagishi M.
      • Takahashi M.
      • Wallingford J.B.
      • Kinoshita M.
      Septin-dependent remodeling of cortical microtubule drives cell reshaping during epithelial wound healing.
      It should be noted that the ability of septins to form multiprotein complexes is not limited to their oligomerization and interactions with actin filaments and microtubules. Published interactomes of different septin family members show a large variety of additional binding partners that include actin-binding proteins, regulators of vesicle trafficking, and signaling molecules such as kinases, phosphatases, and small GTPases.
      • Hecht M.
      • Rosler R.
      • Wiese S.
      • Johnsson N.
      • Gronemeyer T.
      An interaction network of the human SEPT9 established by quantitative mass spectrometry.
      ,
      • Neubauer K.
      • Zieger B.
      The mammalian septin interactome.
      However, functional significance of the majority of these interactions remains to be established.
      Another key molecular feature of the septin oligomers is their affinity to lipid membranes. Mammalian septins preferentially bind to phosphoinositides on different cellular membranes.
      • Akil A.
      • Peng J.
      • Omrane M.
      • Gondeau C.
      • Desterke C.
      • Marin M.
      • Tronchère H.
      • Taveneau C.
      • Sar S.
      • Briolotti P.
      • Benjelloun S.
      • Benjouad A.
      • Maurel P.
      • Thiers V.
      • Bressanelli S.
      • Samuel D.
      • Bréchot C.
      • Gassama-Diagne A.
      Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV.
      ,
      • Omrane M.
      • Camara A.S.
      • Taveneau C.
      • Benzoubir N.
      • Tubiana T.
      • Yu J.
      • Guérois R.
      • Samuel D.
      • Goud B.
      • Poüs C.
      • Bressanelli S.
      • Garratt R.C.
      • Thiam A.R.
      • Gassama-Diagne A.
      Septin 9 has two polybasic domains critical to septin filament assembly and Golgi integrity.
      Such binding could be essential for the annealing of short septin oligomers and assembly of higher order polymeric structures.
      • Bridges A.A.
      • Zhang H.
      • Mehta S.B.
      • Occhipinti P.
      • Tani T.
      • Gladfelter A.S.
      Septin assemblies form by diffusion-driven annealing on membranes.
      Interestingly, septins have been identified among the very few eukaryotic proteins that can sense a micron-scale membrane curvature.
      • Beber A.
      • Taveneau C.
      • Nania M.
      • Tsai F.-C.
      • Di Cicco A.
      • Bassereau P.
      • Lévy D.
      • Cabral J.T.
      • Isambert H.
      • Mangenot S.
      • Bertin A.
      Membrane reshaping by micrometric curvature sensitive septin filaments.
      • Bridges A.A.
      • Jentzsch M.S.
      • Oakes P.W.
      • Occhipinti P.
      • Gladfelter A.S.
      Micron-scale plasma membrane curvature is recognized by the septin cytoskeleton.
      • Cannon K.S.
      • Woods B.L.
      • Crutchley J.M.
      • Gladfelter A.S.
      An amphipathic helix enables septins to sense micrometer-scale membrane curvature.
      Because of this, septin polymers preferentially assemble at the curvature-associated cellular structures such as cytokinetic furrows, bases of dendritic spines in neurons, branches in filamentous fungi, and intracellular lipid droplets.
      • Akil A.
      • Peng J.
      • Omrane M.
      • Gondeau C.
      • Desterke C.
      • Marin M.
      • Tronchère H.
      • Taveneau C.
      • Sar S.
      • Briolotti P.
      • Benjelloun S.
      • Benjouad A.
      • Maurel P.
      • Thiers V.
      • Bressanelli S.
      • Samuel D.
      • Bréchot C.
      • Gassama-Diagne A.
      Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV.
      ,
      • Bridges A.A.
      • Jentzsch M.S.
      • Oakes P.W.
      • Occhipinti P.
      • Gladfelter A.S.
      Micron-scale plasma membrane curvature is recognized by the septin cytoskeleton.
      ,
      • Cannon K.S.
      • Woods B.L.
      • Crutchley J.M.
      • Gladfelter A.S.
      An amphipathic helix enables septins to sense micrometer-scale membrane curvature.
      Septin–membrane interactions not only promote assembly of higher-order septin cytoskeletal structures, but also significantly affect the membrane organization. For example, septin binding can induce membrane deformation, thereby controlling the shape of cellular organelles and vesicles.
      • Omrane M.
      • Camara A.S.
      • Taveneau C.
      • Benzoubir N.
      • Tubiana T.
      • Yu J.
      • Guérois R.
      • Samuel D.
      • Goud B.
      • Poüs C.
      • Bressanelli S.
      • Garratt R.C.
      • Thiam A.R.
      • Gassama-Diagne A.
      Septin 9 has two polybasic domains critical to septin filament assembly and Golgi integrity.
      ,
      • Beber A.
      • Taveneau C.
      • Nania M.
      • Tsai F.-C.
      • Di Cicco A.
      • Bassereau P.
      • Lévy D.
      • Cabral J.T.
      • Isambert H.
      • Mangenot S.
      • Bertin A.
      Membrane reshaping by micrometric curvature sensitive septin filaments.
      Furthermore, membrane-associated septin polymers create physical barriers for the lateral diffusion of lipids and transmembrane proteins, enabling formation of distinct membrane compartments.
      • Caudron F.
      • Barral Y.
      Septins and the lateral compartmentalization of eukaryotic membranes.
      Finally, due to their dual affinity to membrane lipids and other cytoskeletal elements, septins physically link cellular membranes to actin filaments and microtubules, thereby creating a higher order cellular architecture.

      Cellular Functions of the Septin Cytoskeleton

      Given the unique ability of septins to engage in multiple interactions at different cellular compartments, it is not surprising that the septin cytoskeleton has been implicated in the regulation of a variety of cellular functions (Figure 1). Because cellular roles of septins have been described in several excellent reviews,
      • Bridges A.A.
      • Gladfelter A.S.
      Septin form and function at the cell cortex.
      ,
      • Dolat L.
      • Hu Q.
      • Spiliotis E.T.
      Septin functions in organ system physiology and pathology.
      this review briefly summarizes their role in tissue inflammation and fibrosis. However, the canonical activity of the septin cytoskeleton in regulating cell division, also essential for septin functions in inflamed tissues has been extensively reviewed elsewhere and not discussed here.
      • Bridges A.A.
      • Gladfelter A.S.
      Septin form and function at the cell cortex.
      ,
      • Dolat L.
      • Hu Q.
      • Spiliotis E.T.
      Septin functions in organ system physiology and pathology.

      Intracellular Vesicular Trafficking

      The prominent lipid-binding ability of septins allows them to act as important regulators of intracellular vesicle trafficking. At the plasma membrane, SEPT2 participates in the formation of macropinosomes that mediate bulk uptake of the surrounding liquids.
      • Dolat L.
      • Spiliotis E.T.
      Septins promote macropinosome maturation and traffic to the lysosome by facilitating membrane fusion.
      SEPT2, SEPT6, and SEPT7 are essential for the intracellular trafficking of internalized liquid cargo by regulating its transit from early to late endosomes and delivery to lysosomes.
      • Dolat L.
      • Spiliotis E.T.
      Septins promote macropinosome maturation and traffic to the lysosome by facilitating membrane fusion.
      ,
      • Traikov S.
      • Stange C.
      • Wassmer T.
      • Paul-Gilloteaux P.
      • Salamero J.
      • Raposo G.
      • Hoflack B.
      Septin6 and septin7 GTP binding proteins regulate AP-3- and ESCRT-dependent multivesicular body biogenesis.
      A different line of evidence has implicated mammalian septins in the control of internalization and intracellular fate of plasma membrane receptors, most notably members of the epidermal growth factor receptor family.
      • Diesenberg K.
      • Beerbaum M.
      • Fink U.
      • Schmieder P.
      • Krauss M.
      SEPT9 negatively regulates ubiquitin-dependent downregulation of EGFR.
      ,
      • Marcus E.A.
      • Tokhtaeva E.
      • Turdikulova S.
      • Capri J.
      • Whitelegge J.P.
      • Scott D.R.
      • Sachs G.
      • Berditchevski F.
      • Vagin O.
      Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells.
      Specifically, binding with SEPT2 or SEPT9 stabilizes these receptors at the plasma membrane and attenuates their ubiquitination and degradation. Modulation of endocytosis and endosomal transit of the internalized molecules represents only one aspect of septin-dependent regulation of vesicle trafficking. In addition, septins are important for the formation of Golgi-derived vesicles and regulation of both constitutive and stimulated protein exocytosis.
      • Omrane M.
      • Camara A.S.
      • Taveneau C.
      • Benzoubir N.
      • Tubiana T.
      • Yu J.
      • Guérois R.
      • Samuel D.
      • Goud B.
      • Poüs C.
      • Bressanelli S.
      • Garratt R.C.
      • Thiam A.R.
      • Gassama-Diagne A.
      Septin 9 has two polybasic domains critical to septin filament assembly and Golgi integrity.
      ,
      • Tokhtaeva E.
      • Capri J.
      • Marcus E.A.
      • Whitelegge J.P.
      • Khuzakhmetova V.
      • Bukharaeva E.
      • Deiss-Yehiely N.
      • Dada L.A.
      • Sachs G.
      • Fernandez-Salas E.
      • Vagin O.
      Septin dynamics are essential for exocytosis.
      The diverse septin-dependent trafficking events indicate that the septin cytoskeleton may play important roles in regulating receptor signaling on the plasma membrane, controlling transmembrane fluxes of ions and metabolites, and regulating protein secretion. The ability of septins to control multiple steps of vesicle trafficking underlies the important functions of the septin cytoskeleton in regulating host–pathogen interactions and deposition of the extracellular matrix in fibrotic tissues as discussed below.

      Cell Migration and Matrix Adhesion

      Another important function of the septin cytoskeleton involves regulation of cell migration. Several studies demonstrate that loss of SEPT2, SEPT7, and SEPT9 consistently attenuates wound healing in cultured epithelial and cancer cell monolayers, as well as in Xenopus embryo.
      • Dolat L.
      • Hunyara J.L.
      • Bowen J.R.
      • Karasmanis E.P.
      • Elgawly M.
      • Galkin V.E.
      • Spiliotis E.T.
      Septins promote stress fiber-mediated maturation of focal adhesions and renal epithelial motility.
      ,
      • Shindo A.
      • Audrey A.
      • Takagishi M.
      • Takahashi M.
      • Wallingford J.B.
      • Kinoshita M.
      Septin-dependent remodeling of cortical microtubule drives cell reshaping during epithelial wound healing.
      ,
      • Zeng Y.
      • Cao Y.
      • Liu L.
      • Zhao J.
      • Zhang T.
      • Xiao L.
      • Jia M.
      • Tian Q.
      • Yu H.
      • Chen S.
      • Cai Y.
      SEPT9_i1 regulates human breast cancer cell motility through cytoskeletal and RhoA/FAK signaling pathway regulation.
      ,
      • Zhang N.
      • Liu L.
      • Fan N.
      • Zhang Q.
      • Wang W.
      • Zheng M.
      • Ma L.
      • Li Y.
      • Shi L.
      The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation.
      The observed promigratory activity of the septin cytoskeleton may be mediated by different mechanisms such as control of cortical microtubule assembly at the migrating cell edge,
      • Shindo A.
      • Audrey A.
      • Takagishi M.
      • Takahashi M.
      • Wallingford J.B.
      • Kinoshita M.
      Septin-dependent remodeling of cortical microtubule drives cell reshaping during epithelial wound healing.
      formation of basal actin-based stress fibers,
      • Dolat L.
      • Hunyara J.L.
      • Bowen J.R.
      • Karasmanis E.P.
      • Elgawly M.
      • Galkin V.E.
      • Spiliotis E.T.
      Septins promote stress fiber-mediated maturation of focal adhesions and renal epithelial motility.
      stabilization of focal adhesions,
      • Dolat L.
      • Hunyara J.L.
      • Bowen J.R.
      • Karasmanis E.P.
      • Elgawly M.
      • Galkin V.E.
      • Spiliotis E.T.
      Septins promote stress fiber-mediated maturation of focal adhesions and renal epithelial motility.
      ,
      • Zeng Y.
      • Cao Y.
      • Liu L.
      • Zhao J.
      • Zhang T.
      • Xiao L.
      • Jia M.
      • Tian Q.
      • Yu H.
      • Chen S.
      • Cai Y.
      SEPT9_i1 regulates human breast cancer cell motility through cytoskeletal and RhoA/FAK signaling pathway regulation.
      and activation of mitogen-activated protein (MAP) kinase signaling.
      • Zhang N.
      • Liu L.
      • Fan N.
      • Zhang Q.
      • Wang W.
      • Zheng M.
      • Ma L.
      • Li Y.
      • Shi L.
      The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation.
      Interestingly, SEPT2 and SEPT9 are not only essential for focal adhesion maturation, but also regulate the assembly of other adhesion structures (such as podosomes), that mediate matrix degradation.
      • Collins K.B.
      • Kang H.
      • Matsche J.
      • Klomp J.E.
      • Rehman J.
      • Malik A.B.
      • Karginov A.V.
      Septin2 mediates podosome maturation and endothelial cell invasion associated with angiogenesis.
      ,
      • Møller A.M.J.
      • Füchtbauer E.-M.
      • Brüel A.
      • Andersen T.L.
      • Borggaard X.G.
      • Pavlos N.J.
      • Thomsen J.S.
      • Pedersen F.S.
      • Delaisse J.M.
      • Søe K.
      Septins are critical regulators of osteoclastic bone resorption.
      As discussed below, septin-dependent regulation of cell migration could be an important contributor to leukocyte infiltration in the inflamed tissues.

      Regulation of Cellular Signaling

      In addition to interacting with other cytoskeletal structures, septins participate in additional protein–protein interactions, thereby regulating different intracellular signaling pathways. Thus, the plasma membrane–endoplasmic reticulum contact sites are important places for the septin activity in mammalian cancer cells and Drosophila neurons, where SEPT2, SEPT4, SEPT5, and SEPT7 control assembly of STIM1-ORAI1 calcium channels and regulate store-operated calcium entry.
      • Deb B.K.
      • Pathak T.
      • Hasan G.
      Store-independent modulation of Ca(2+) entry through Orai by septin 7.
      ,
      • Sharma S.
      • Quintana A.
      • Findlay G.M.
      • Mettlen M.
      • Baust B.
      • Jain M.
      • Nilsson R.
      • Rao A.
      • Hogan P.G.
      An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry.
      SEPT4 has recently been identified as a novel regulator of a signal transducer and activator of transcription (STAT) 3 activity in vascular smooth muscle cells.
      • Zhang N.
      • Zhang Y.
      • You S.
      • Tian Y.
      • Lu S.
      • Cao L.
      • Sun Y.
      Septin4 prevents PDGF-BB-induced HAVSMC phenotypic transformation, proliferation and migration by promoting SIRT1-STAT3 deacetylation and dephosphorylation.
      SEPT4 binds to STAT3 and promotes its interaction with SIRT1 deacetylase, which results in inhibition of STAT3-mediated signaling.
      • Zhang N.
      • Zhang Y.
      • You S.
      • Tian Y.
      • Lu S.
      • Cao L.
      • Sun Y.
      Septin4 prevents PDGF-BB-induced HAVSMC phenotypic transformation, proliferation and migration by promoting SIRT1-STAT3 deacetylation and dephosphorylation.
      In contrast to STAT3 inhibition, septin binding may promote MAP kinase-dependent signaling, as supported by the direct interaction of the SEPT9_v1 isoform with c-Jun N-terminal kinase (JNK) in human mammary epithelial cells, protecting it from degradation and increasing kinase activity.
      • Gonzalez M.E.
      • Makarova O.
      • Peterson E.A.
      • Privette L.M.
      • Petty E.M.
      Up-regulation of SEPT9_v1 stabilizes c-Jun-N-terminal kinase and contributes to its pro-proliferative activity in mammary epithelial cells.
      This results in a marked enhancement of JNK-dependent gene expression. Similarly, the protective effects of septin binding have significant functional consequences for hypoxia-inducible factor-1 (HIF-1) signaling. SEPT9_v1 is an important binding partner for HIF-1α in human cancer cell lines.
      • Amir S.
      • Golan M.
      • Mabjeesh N.J.
      Targeted knockdown of SEPT9_v1 inhibits tumor growth and angiogenesis of human prostate cancer cells concomitant with disruption of hypoxia-inducible factor-1 pathway.
      ,
      • Amir S.
      • Wang R.
      • Matzkin H.
      • Simons J.W.
      • Mabjeesh N.J.
      MSF-A interacts with hypoxia-inducible factor-1alpha and augments hypoxia-inducible factor transcriptional activation to affect tumorigenicity and angiogenesis.
      This interaction protects HIF-1α protein from ubiquitination and degradation under normoxic and hypoxic conditions and markedly enhances its transcriptional activity.
      • Amir S.
      • Wang R.
      • Matzkin H.
      • Simons J.W.
      • Mabjeesh N.J.
      MSF-A interacts with hypoxia-inducible factor-1alpha and augments hypoxia-inducible factor transcriptional activation to affect tumorigenicity and angiogenesis.
      The septin-dependent regulation of STAT3, JNK, and HIF-1α signaling could be particularly important during mucosal inflammation where these signaling events are markedly up-regulated by proinflammatory cytokines and tissue hypoxia.
      • López-Posadas R.
      • Neurath M.F.
      • Atreya I.
      Molecular pathways driving disease-specific alterations of intestinal epithelial cells.
      ,
      • Taylor C.T.
      • Colgan S.P.
      Regulation of immunity and inflammation by hypoxia in immunological niches.

      Septin-Dependent Regulation of Inflammation and Tissue Fibrosis

      Since the discovery of the first septins in yeast cells more than 30 years ago, these proteins have been extensively studied by cell and developmental biologists. Recently, it became clear that abnormal organization and regulation of the septin cytoskeleton may contribute to the pathophysiology of different human diseases. The main focus in these studies is on understanding the roles of septin dysfunction in the development of neurodegenerative diseases and cancer.
      • Angelis D.
      • Spiliotis E.T.
      Septin mutations in human cancers.
      ,
      • Marttinen M.
      • Kurkinen K.M.
      • Soininen H.
      • Haapasalo A.
      • Hiltunen M.
      Synaptic dysfunction and septin protein family members in neurodegenerative diseases.
      ,
      • Poüs C.
      • Klipfel L.
      • Baillet A.
      Cancer-related functions and subcellular localizations of septins.
      Although several lines of evidence strongly suggest roles of septins in inflammatory disorders, very little is known about the specfics of those roles. The most plausible functions of the septin cytoskeleton during tissue inflammation are discussed below. They involve regulation of pathogen uptake, control of immune cell infiltration and activity, regulation of tissue barrier permeability, and contribution to tissue fibrosis. A summary of these functions can be found in Table 1 and Figure 2.
      Table 1Functional Effects of Targeting Different Septins on Experimental Infection, Inflammation, and Fibrosis Models
      Septin paralogInterference with the septin cytoskeletonExperimental systemEffects of the septin cytoskeleton perturbationReference
      Host–pathogen interactions
       SEPT2siRNA-mediated knockdownHeLa cervical epithelial cells, JEG-3 trophoblast cellsInhibited Listeria and Shigella invasion
      • Mostowy S.
      • Nam Tham T.
      • Danckaert A.
      • Guadagnini S.
      • Boisson-Dupuis S.
      • Pizarro-Cerdá J.
      • Cossart P.
      Septins regulate bacterial entry into host cells.
       SEPT2, SEPT7, SEPT9siRNA-mediated knockdownHeLa cellsInhibited Salmonella invasion
      • Boddy K.C.
      • Gao A.D.
      • Truong D.
      • Kim M.S.
      • Froese C.D.
      • Trimble W.S.
      • Brumell J.H.
      Septin-regulated actin dynamics promote Salmonella invasion of host cells.
       SEPT7siRNA-mediated knockdownHuman endothelial cellsInhibited Candida endocytosis
      • Phan Q.T.
      • Eng D.K.
      • Mostowy S.
      • Park H.
      • Cossart P.
      • Filler S.G.
      Role of endothelial cell septin 7 in the endocytosis of Candida albicans.
       SEPT9siRNA-mediated knockdownHeLa cellsInhibited enteropathogenic Escherichia coli attachment
      • Scholz R.
      • Imami K.
      • Scott N.E.
      • Trimble W.S.
      • Foster L.J.
      • Finlay B.B.
      Novel host proteins and signaling pathways in enteropathogenic E. coli pathogenesis identified by global phosphoproteome analysis.
       SEPT2, SEPT7siRNA-mediated knockdownHeLa cellsIncreased survival and proliferation of intracellular Shigella
      • Lobato-Márquez D.
      • Krokowski S.
      • Sirianni A.
      • Larrouy-Maumus G.
      • Mostowy S.
      A requirement for septins and the autophagy receptor p62 in the proliferation of intracellular Shigella.
      ,
      • Sirianni A.
      • Krokowski S.
      • Lobato-Márquez D.
      • Buranyi S.
      • Pfanzelter J.
      • Galea D.
      • Willis A.
      • Culley S.
      • Henriques R.
      • Larrouy-Maumus G.
      • Hollinshead M.
      • Sancho-Shimizu V.
      • Way M.
      • Mostowy S.
      Mitochondria mediate septin cage assembly to promote autophagy of Shigella.
       SEPT2, SEPT7, SEPT9siRNA-mediated knockdownHeLa cellsInhibited Chlamydia extrusion by host cells
      • Volceanov L.
      • Herbst K.
      • Biniossek M.
      • Schilling O.
      • Haller D.
      • Nölke T.
      • Subbarayal P.
      • Rudel T.
      • Zieger B.
      • Häcker G.
      Septins arrange F-actin-containing fibers on the Chlamydia trachomatis inclusion and are required for normal release of the inclusion by extrusion.
       SEPT7siRNA-mediated knockdownA549 lung epithelial cellsAccelerated vaccinia virus release from host cells
      • Pfanzelter J.
      • Mostowy S.
      • Way M.
      Septins suppress the release of vaccinia virus from infected cells.
       SEPT9siRNA-mediated knockdownHuh7 liver epithelial cellsInhibited hepatitis C virus (HCV) replication
      • Akil A.
      • Peng J.
      • Omrane M.
      • Gondeau C.
      • Desterke C.
      • Marin M.
      • Tronchère H.
      • Taveneau C.
      • Sar S.
      • Briolotti P.
      • Benjelloun S.
      • Benjouad A.
      • Maurel P.
      • Thiers V.
      • Bressanelli S.
      • Samuel D.
      • Bréchot C.
      • Gassama-Diagne A.
      Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV.
       SEPT7Morpholino-mediated knockdownZebrafish larvaeIncreased susceptibility to Shigella infection
      • Mazon-Moya M.J.
      • Willis A.R.
      • Torraca V.
      • Boucontet L.
      • Shenoy A.R.
      • Colucci-Guyon E.
      • Mostowy S.
      Septins restrict inflammation and protect zebrafish larvae from Shigella infection.
      Immune cell development and tissue barrier integrity
       SEPT2small harpin (sh)RNA-mediated knockdownHeLa cells, RAW264.7 macrophagesInhibited Fc receptor–mediated phagocytosis
      • Huang Y.W.
      • Yan M.
      • Collins R.F.
      • Diciccio J.E.
      • Grinstein S.
      • Trimble W.S.
      Mammalian septins are required for phagosome formation.
       SEPT7shRNA-mediated knockdownD10.G4 T-cell lineDecreased spontaneous crawling velocity. Increased transmigration through porous membrane
      • Tooley A.J.
      • Gilden J.
      • Jacobelli J.
      • Beemiller P.
      • Trimble W.S.
      • Kinoshita M.
      • Krummel M.F.
      Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility.
       SEPT7T-cell–specific knockoutMiceDeclines T-cell population in vivo. Inhibited proliferation of stimulated T cells
      • Mujal A.M.
      • Gilden J.K.
      • Gerard A.
      • Kinoshita M.
      • Krummel M.F.
      A septin requirement differentiates autonomous and contact-facilitated T cell proliferation.
       SEPT9T-cell–specific knockoutMiceDecreased mature T-cell number in vivo
      • Lassen L.B.
      • Füchtbauer A.
      • Schmitz A.
      • Sørensen A.B.
      • Pedersen F.S.
      • Füchtbauer E.-M.
      Septin9 is involved in T-cell development and CD8+ T-cell homeostasis.
       SEPT2shRNA-mediated knockdownPrimary human bronchial epithelial cellsIncreased epithelial permeability
      • Sidhaye V.K.
      • Chau E.
      • Breysse P.N.
      • King L.S.
      Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions.
       SEPT7Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9–mediated knockoutHT-29 human colonic epithelial cellsIncreased epithelial permeability
      • Sun L.
      • Cao X.
      • Lechuga S.
      • Feygin A.
      • Naydenov N.G.
      • Ivanov A.I.
      A septin cytoskeleton-targeting small molecule, forchlorfenuron, inhibits epithelial migration via septin-independent perturbation of cellular signaling.
       SEPT2shRNA-mediated knockdownPrimary human endothelial cellsIncreased endothelial permeability. Accelerated leukocyte transmigration
      • Kim J.
      • Cooper J.A.
      Septins regulate junctional integrity of endothelial monolayers.
       SEPT2siRNA-mediated knockdownPrimary human endothelial cellsExaggeration of thrombin-induced barrier breakdown
      • Amado-Azevedo J.
      • de Menezes R.X.
      • van Nieuw Amerongen G.P.
      • van Hinsbergh V.W.M.
      • Hordijk P.L.
      A functional siRNA screen identifies RhoGTPase-associated genes involved in thrombin-induced endothelial permeability.
      Tissue fibrosis
       SEPT4Whole-body knockoutMiceMore severe liver fibrosis in 3 in vivo models
      • Iwaisako K.
      • Hatano E.
      • Taura K.
      • Nakajima A.
      • Tada M.
      • Seo S.
      • Tamaki N.
      • Sato F.
      • Ikai I.
      • Uemoto S.
      • Kinoshita M.
      Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells.
       SEPT4Adenovirus-mediated overexpressionMiceSuppression of Schistosoma-induced liver fibrosis
      • He X.
      • Bao J.
      • Chen J.
      • Sun X.
      • Wang J.
      • Zhu D.
      • Song K.
      • Peng W.
      • Xu T.
      • Duan Y.
      Adenovirus-mediated over-expression of Septin4 ameliorates hepatic fibrosis in mouse livers infected with Schistosoma japonicum.
       SEPT6shRNA-mediated knockdownMiceSuppression of thioacetamide-induced liver fibrosis
      • Fan Y.
      • Du Z.
      • Steib C.J.
      • Ding Q.
      • Lu P.
      • Tian D.
      • Liu M.
      Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism.
       SEPT8Whole-body knockoutMiceNo effect on the unilateral ureteral obstruction model of kidney fibrosis
      • Neubauer K.
      • Neubauer B.
      • Seidl M.
      • Zieger B.
      Characterization of septin expression in normal and fibrotic kidneys.
      Figure thumbnail gr2
      Figure 2Mechanisms of regulation of inflammation and fibrosis through septins. This figure depicts the known or proposed impact of septins on: TGF-β and MAP kinase signaling (1); pathogen invasion, processing, and dissemination (2); exocytosis and assembly of extracellular matrix proteins (3); and immune cell migration (4). SEPT, septin; TGF-β, transforming growth factor-β.

      Host–Pathogen Interactions

      Septin-dependent regulation of host–pathogen interactions have been initially alluded to by a study that identified SEPT9 as a major protein enriched in phagosomes responsible for the cellular entry of Listeria monocytogenes.
      • Pizarro-Cerdá J.
      • Jonquières R.
      • Gouin E.
      • Vandekerckhove J.
      • Garin J.
      • Cossart P.
      Distinct protein patterns associated with Listeria monocytogenes InlA- or InlB-phagosomes.
      Subsequent studies showed crucial regulatory roles of the septin cytoskeleton during infection of cultured mammalian cells with different bacterial, fungal, or viral pathogens.
      • Mostowy S.
      • Cossart P.
      Septins: the fourth component of the cytoskeleton.
      ,
      • Torraca V.
      • Mostowy S.
      Septins and bacterial infection.
      Interestingly, septins appear to have a dual role in controlling pathogen invasion and spread in the host cells. On the one hand, pathogens hijack the septin cytoskeleton to invade the host cells, as supported by septin accumulation at the pathogen entry sites during L. monocytogenes, Shigella flexneri, Salmonella typhimurium, and Candida albicans invasion.
      • Mostowy S.
      • Nam Tham T.
      • Danckaert A.
      • Guadagnini S.
      • Boisson-Dupuis S.
      • Pizarro-Cerdá J.
      • Cossart P.
      Septins regulate bacterial entry into host cells.
      • Boddy K.C.
      • Gao A.D.
      • Truong D.
      • Kim M.S.
      • Froese C.D.
      • Trimble W.S.
      • Brumell J.H.
      Septin-regulated actin dynamics promote Salmonella invasion of host cells.
      • Phan Q.T.
      • Eng D.K.
      • Mostowy S.
      • Park H.
      • Cossart P.
      • Filler S.G.
      Role of endothelial cell septin 7 in the endocytosis of Candida albicans.
      On the other hand, depletion of key septin paralogs, such as SEPT2, SEPT7, and SEPT9, markedly inhibits internalization of these bacterial pathogens.
      • Mostowy S.
      • Nam Tham T.
      • Danckaert A.
      • Guadagnini S.
      • Boisson-Dupuis S.
      • Pizarro-Cerdá J.
      • Cossart P.
      Septins regulate bacterial entry into host cells.
      • Boddy K.C.
      • Gao A.D.
      • Truong D.
      • Kim M.S.
      • Froese C.D.
      • Trimble W.S.
      • Brumell J.H.
      Septin-regulated actin dynamics promote Salmonella invasion of host cells.
      • Phan Q.T.
      • Eng D.K.
      • Mostowy S.
      • Park H.
      • Cossart P.
      • Filler S.G.
      Role of endothelial cell septin 7 in the endocytosis of Candida albicans.
      Although mechanisms underlying septin-dependent regulation of bacterial entry remain poorly investigated, they likely involve remodeling of the cortical actin cytoskeleton. Thus, SEPT7 mediates recruitment of an important actin cytoskeletal regulator, Rho-associated kinase 2, to the S. typhimurium entry sites and promotes Salmonella-induced phosphorylation of the actin polymerizing protein, formin homology domain containing-1.
      • Boddy K.C.
      • Gao A.D.
      • Truong D.
      • Kim M.S.
      • Froese C.D.
      • Trimble W.S.
      • Brumell J.H.
      Septin-regulated actin dynamics promote Salmonella invasion of host cells.
      Additionally, atomic force microscopy indicates decreased viscosity and elasticity of the cell cortex following SEPT2 or SEPT11 depletion, which is consistent with altered organization of the submembranous actin cytoskeleton.
      • Mostowy S.
      • Janel S.
      • Forestier C.
      • Roduit C.
      • Kasas S.
      • Pizarro-Cerdá J.
      • Cossart P.
      • Lafont F.
      A role for septins in the interaction between the Listeria monocytogenes invasion protein InlB and the Met receptor.
      Altered organization of the cortical actin cytoskeleton in septin-deficient cells can also explain the inhibitory effects of SEPT9 depletion on the attachment of enteropathogenic Escherichia coli, which requires extensive cytoskeletal remodeling of the host cell.
      • Scholz R.
      • Imami K.
      • Scott N.E.
      • Trimble W.S.
      • Foster L.J.
      • Finlay B.B.
      Novel host proteins and signaling pathways in enteropathogenic E. coli pathogenesis identified by global phosphoproteome analysis.
      Despite accelerating pathogen entry, septin cytoskeleton also acts as a negative regulator of infection by limiting survival and spread of intracellular pathogens. Septin filament assembly entraps a significant fraction of intracytosolic Shigella, including actively dividing bacteria.
      • Krokowski S.
      • Lobato-Márquez D.
      • Chastanet A.
      • Pereira P.M.
      • Angelis D.
      • Galea D.
      • Larrouy-Maumus G.
      • Henriques R.
      • Spiliotis E.T.
      • Carballido-López R.
      • Mostowy S.
      Septins recognize and entrap dividing bacterial cells for delivery to lysosomes.
      ,
      • Mostowy S.
      • Bonazzi M.
      • Hamon M.A.
      • Tham T.N.
      • Mallet A.
      • Lelek M.
      • Gouin E.
      • Demangel C.
      • Brosch R.
      • Zimmer C.
      • Sartori A.
      • Kinoshita M.
      • Lecuit M.
      • Cossart P.
      Entrapment of intracytosolic bacteria by septin cage-like structures.
      This septin caging inhibits bacterial metabolism, proliferation, and motility inside the host cells.
      • Lobato-Márquez D.
      • Krokowski S.
      • Sirianni A.
      • Larrouy-Maumus G.
      • Mostowy S.
      A requirement for septins and the autophagy receptor p62 in the proliferation of intracellular Shigella.
      ,
      • Sirianni A.
      • Krokowski S.
      • Lobato-Márquez D.
      • Buranyi S.
      • Pfanzelter J.
      • Galea D.
      • Willis A.
      • Culley S.
      • Henriques R.
      • Larrouy-Maumus G.
      • Hollinshead M.
      • Sancho-Shimizu V.
      • Way M.
      • Mostowy S.
      Mitochondria mediate septin cage assembly to promote autophagy of Shigella.
      ,
      • Mostowy S.
      • Bonazzi M.
      • Hamon M.A.
      • Tham T.N.
      • Mallet A.
      • Lelek M.
      • Gouin E.
      • Demangel C.
      • Brosch R.
      • Zimmer C.
      • Sartori A.
      • Kinoshita M.
      • Lecuit M.
      • Cossart P.
      Entrapment of intracytosolic bacteria by septin cage-like structures.
      More importantly, assembled septin cages recruit components of the autophagosomal machinery that accelerates the delivery of entrapped Shigella into lysosomes for degradation.
      • Krokowski S.
      • Lobato-Márquez D.
      • Chastanet A.
      • Pereira P.M.
      • Angelis D.
      • Galea D.
      • Larrouy-Maumus G.
      • Henriques R.
      • Spiliotis E.T.
      • Carballido-López R.
      • Mostowy S.
      Septins recognize and entrap dividing bacterial cells for delivery to lysosomes.
      ,
      • Mostowy S.
      • Bonazzi M.
      • Hamon M.A.
      • Tham T.N.
      • Mallet A.
      • Lelek M.
      • Gouin E.
      • Demangel C.
      • Brosch R.
      • Zimmer C.
      • Sartori A.
      • Kinoshita M.
      • Lecuit M.
      • Cossart P.
      Entrapment of intracytosolic bacteria by septin cage-like structures.
      Formation of septin cages is not a unique event of Shigella infection, and also occurs during invasion of other intracellular pathogens. For example, septin filament network assembles around intracellular vacuoles containing Chlamydia trachomatis in human epithelial cells
      • Volceanov L.
      • Herbst K.
      • Biniossek M.
      • Schilling O.
      • Haller D.
      • Nölke T.
      • Subbarayal P.
      • Rudel T.
      • Zieger B.
      • Häcker G.
      Septins arrange F-actin-containing fibers on the Chlamydia trachomatis inclusion and are required for normal release of the inclusion by extrusion.
      and internalized enteropathogenic E. coli in macrophages.
      • Lee P.P.
      • Lobato-Márquez D.
      • Pramanik N.
      • Sirianni A.
      • Daza-Cajigal V.
      • Rivers E.
      • Cavazza A.
      • Bouma G.
      • Moulding D.
      • Hultenby K.
      • Westerberg L.S.
      • Hollinshead M.
      • Lau Y.-L.
      • Burns S.O.
      • Mostowy S.
      • Bajaj-Elliott M.
      • Thrasher A.J.
      Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells.
      Furthermore, during vaccinia virus infection, septin filaments wrap around newly assembled virions attached to the host cell surface, forming cage-like structures.
      • Pfanzelter J.
      • Mostowy S.
      • Way M.
      Septins suppress the release of vaccinia virus from infected cells.
      Interestingly, encaging of Chlamydia and vaccinia virus by the host septin cytoskeleton has opposite effects on the pathogen release from the host cells. Specifically, the septin cytoskeleton prevents vaccinia virus release and cell-to-cell dissemination while promoting Chlamydia extrusion.
      • Volceanov L.
      • Herbst K.
      • Biniossek M.
      • Schilling O.
      • Haller D.
      • Nölke T.
      • Subbarayal P.
      • Rudel T.
      • Zieger B.
      • Häcker G.
      Septins arrange F-actin-containing fibers on the Chlamydia trachomatis inclusion and are required for normal release of the inclusion by extrusion.
      ,
      • Pfanzelter J.
      • Mostowy S.
      • Way M.
      Septins suppress the release of vaccinia virus from infected cells.
      Finally, a different mechanism exploiting the lipid-binding ability of the septin cytoskeleton was shown to drive hepatitis C virus (HCV) infection of liver cells.
      • Akil A.
      • Peng J.
      • Omrane M.
      • Gondeau C.
      • Desterke C.
      • Marin M.
      • Tronchère H.
      • Taveneau C.
      • Sar S.
      • Briolotti P.
      • Benjelloun S.
      • Benjouad A.
      • Maurel P.
      • Thiers V.
      • Bressanelli S.
      • Samuel D.
      • Bréchot C.
      • Gassama-Diagne A.
      Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV.
      HCV infection markedly accelerates SEPT9 expression and septin filament assembly. This results in accumulation of intracellular lipid droplets, which is dependent on septin filament interactions with phosphoinositide and microtubules. Such septin-driven formation of lipid droplets is crucial for efficient HCV replication.
      • Akil A.
      • Peng J.
      • Omrane M.
      • Gondeau C.
      • Desterke C.
      • Marin M.
      • Tronchère H.
      • Taveneau C.
      • Sar S.
      • Briolotti P.
      • Benjelloun S.
      • Benjouad A.
      • Maurel P.
      • Thiers V.
      • Bressanelli S.
      • Samuel D.
      • Bréchot C.
      • Gassama-Diagne A.
      Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV.
      While a growing number of studies focus on the septin-dependent regulation of pathogen interactions with cultured cells in vitro, almost nothing is known about the ability of the septin cytoskeleton to regulate pathogen infection in vivo. The only study addressing this reported that septins restrict Shigella infection and the associated inflammatory response in zebrafish larvae.
      • Mazon-Moya M.J.
      • Willis A.R.
      • Torraca V.
      • Boucontet L.
      • Shenoy A.R.
      • Colucci-Guyon E.
      • Mostowy S.
      Septins restrict inflammation and protect zebrafish larvae from Shigella infection.
      In this study, loss of SEPT7 increased bacterial burden, which was linked to overactivation of IL-1β signaling and increase in bacteria-induced neutrophil death.
      • Mazon-Moya M.J.
      • Willis A.R.
      • Torraca V.
      • Boucontet L.
      • Shenoy A.R.
      • Colucci-Guyon E.
      • Mostowy S.
      Septins restrict inflammation and protect zebrafish larvae from Shigella infection.
      Interestingly, pharmacologic inhibition of the inflammatory response using IL-1 receptor antagonist rescued neutrophil survival and decreased bacterial burden in septin-deficient zebrafish. Together, these studies strongly suggest that the septin cytoskeleton could serve as an important regulator of host–pathogen interactions and inflammatory responses triggered by bacterial or viral infections.

      Immune Cell Development and Functions

      Different septin paralogs are abundantly expressed in human macrophages, lymphocytes, and dendritic cells.
      • Huang Y.W.
      • Yan M.
      • Collins R.F.
      • Diciccio J.E.
      • Grinstein S.
      • Trimble W.S.
      Mammalian septins are required for phagosome formation.
      ,
      • Tooley A.J.
      • Gilden J.
      • Jacobelli J.
      • Beemiller P.
      • Trimble W.S.
      • Kinoshita M.
      • Krummel M.F.
      Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility.
      ,
      • Sui L.
      • Zhang W.
      • Liu Q.
      • Chen T.
      • Li N.
      • Wan T.
      • Yu M.
      • Cao X.
      Cloning and functional characterization of human septin 10, a novel member of septin family cloned from dendritic cells.
      However, the role of the septin cytoskeleton in regulation of immune cell development and functions remains poorly understood (Table 1). In macrophages, SEPT2 and SEPT11 accumulate at the phagosomes in actin cytoskeleton-dependent fashion, and SEPT2 depletion was shown to inhibit Fc receptor–mediated phagocytosis.
      • Huang Y.W.
      • Yan M.
      • Collins R.F.
      • Diciccio J.E.
      • Grinstein S.
      • Trimble W.S.
      Mammalian septins are required for phagosome formation.
      Disruption of the septin cytoskeleton by SEPT7 depletion causes profound alterations in T lymphocyte cell morphology manifested by the excessive membrane blebbing and increased uropod length.
      • Tooley A.J.
      • Gilden J.
      • Jacobelli J.
      • Beemiller P.
      • Trimble W.S.
      • Kinoshita M.
      • Krummel M.F.
      Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility.
      ,
      • Gilden J.K.
      • Peck S.
      • Chen Y.C.
      • Krummel M.F.
      The septin cytoskeleton facilitates membrane retraction during motility and blebbing.
      The disruption of the septin cytoskeleton also has a complex effect on T-cell motility such that SEPT7-deficient T cells exhibit decreased crawling velocity during random planar migration, but are able to more efficiently transmigrate through confined spaces, such as the small pores in the Transwell membrane filters.
      • Tooley A.J.
      • Gilden J.
      • Jacobelli J.
      • Beemiller P.
      • Trimble W.S.
      • Kinoshita M.
      • Krummel M.F.
      Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility.
      It has been suggested that decreased rigidity of the cell cortex in septin-deficient T cells increases the ability of the cell membrane to form protrusions, which impairs the processive and directional movement of the cell in open spaces. By contrast, such cortical destabilization allows for higher deformability of septin-depleted cells that accelerates their passing through narrow spaces.
      • Tooley A.J.
      • Gilden J.
      • Jacobelli J.
      • Beemiller P.
      • Trimble W.S.
      • Kinoshita M.
      • Krummel M.F.
      Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility.
      ,
      • Gilden J.
      • Krummel M.F.
      Control of cortical rigidity by the cytoskeleton: emerging roles for septins.
      Disruption of the septin cytoskeleton negatively impacts other aspects of T-cell development and functions. Thus, transgenic mice with T-cell–specific ablation of SEPT9 are characterized by a decreased number of mature peripheral T cells, especially the CD8+ T-cell population.
      • Lassen L.B.
      • Füchtbauer A.
      • Schmitz A.
      • Sørensen A.B.
      • Pedersen F.S.
      • Füchtbauer E.-M.
      Septin9 is involved in T-cell development and CD8+ T-cell homeostasis.
      These maturation defects are associated with the decreased proliferation capacity of SEPT9-deficient CD8+ T cells. Similarly, conditional knockout of SEPT7 in T lymphocytes results in the diminished CD8+ cell population in aged mice.
      • Mujal A.M.
      • Gilden J.K.
      • Gerard A.
      • Kinoshita M.
      • Krummel M.F.
      A septin requirement differentiates autonomous and contact-facilitated T cell proliferation.
      Additionally, isolated SEPT7-deficient CD8+ T cells show markedly reduced proliferation and cytokinesis failure after stimulation with soluble immune activators such as cytokines, phorbol ester, or ionomycin.
      • Mujal A.M.
      • Gilden J.K.
      • Gerard A.
      • Kinoshita M.
      • Krummel M.F.
      A septin requirement differentiates autonomous and contact-facilitated T cell proliferation.

      Regulation of Tissue Barriers

      In addition to playing important roles in regulating pathogen engagement and immune cell responses, septin cytoskeleton serves as essential regulator of the integrity and permeability of tissue barriers (Table 1). Indeed, disruption of epithelial and vascular endothelial barriers is a common feature of different inflammatory processes.
      • Peng Z.
      • Shu B.
      • Zhang Y.
      • Wang M.
      Endothelial response to pathophysiological stress.
      ,
      • Zuo L.
      • Kuo W.T.
      • Turner J.R.
      Tight junctions as targets and effectors of mucosal immune homeostasis.
      Limited and transient increased barrier permeability has beneficial effects by allowing tissue influx of immune cells and efficient pathogen clearance. However, poorly controlled and prolonged disruption of epithelial and endothelial barriers is detrimental because it increases body exposure to environmental pathogens and stressors, and exaggerates the inflammatory response.
      • Peng Z.
      • Shu B.
      • Zhang Y.
      • Wang M.
      Endothelial response to pathophysiological stress.
      ,
      • Zuo L.
      • Kuo W.T.
      • Turner J.R.
      Tight junctions as targets and effectors of mucosal immune homeostasis.
      Permeability of epithelial and endothelial barriers is regulated by specialized adhesive structures, adherens and tight junctions, which are regulated by the underlying cortical actomyosin cytoskeleton.
      • Lechuga S.
      • Ivanov A.I.
      Disruption of the epithelial barrier during intestinal inflammation: quest for new molecules and mechanisms.
      ,
      • Schnoor M.
      • Garcia Ponce A.
      • Vadillo E.
      • Pelayo R.
      • Rossaint J.
      • Zarbock A.
      Actin dynamics in the regulation of endothelial barrier functions and neutrophil recruitment during endotoxemia and sepsis.
      ,
      • Ivanov A.I.
      • Parkos C.A.
      • Nusrat A.
      Cytoskeletal regulation of epithelial barrier function during inflammation.
      Emerging evidence suggests that the septin cytoskeleton acts as an important regulator of epithelial and endothelial junctions. For example, SEPT2 is enriched at intercellular junctions in cultured human endothelial
      • Kim J.
      • Cooper J.A.
      Septins regulate junctional integrity of endothelial monolayers.
      and bronchial epithelial cells.
      • Sidhaye V.K.
      • Chau E.
      • Breysse P.N.
      • King L.S.
      Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions.
      Down-regulation of SEPT2 and SEPT7 expression increases permeability of model bronchial and intestinal epithelial cell monolayers, respectively.
      • Sun L.
      • Cao X.
      • Lechuga S.
      • Feygin A.
      • Naydenov N.G.
      • Ivanov A.I.
      A septin cytoskeleton-targeting small molecule, forchlorfenuron, inhibits epithelial migration via septin-independent perturbation of cellular signaling.
      ,
      • Sidhaye V.K.
      • Chau E.
      • Breysse P.N.
      • King L.S.
      Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions.
      In vascular endothelium, loss of SEPT2 accelerates leakiness of a resting endothelial barrier,
      • Kim J.
      • Cooper J.A.
      Septins regulate junctional integrity of endothelial monolayers.
      as well as exaggerates barrier disruption and attenuates barrier recovery following endothelial stimulation with thrombin.
      • Amado-Azevedo J.
      • de Menezes R.X.
      • van Nieuw Amerongen G.P.
      • van Hinsbergh V.W.M.
      • Hordijk P.L.
      A functional siRNA screen identifies RhoGTPase-associated genes involved in thrombin-induced endothelial permeability.
      Interestingly, increased vascular permeability of SEPT2-depleted endothelium promotes transendothelial migration of natural killer cells.
      • Kim J.
      • Cooper J.A.
      Septins regulate junctional integrity of endothelial monolayers.
      Furthermore, loss of SEPT2 sensitizes bronchial epithelial cells to the barrier-disruptive action of an environmental hazard, particulate matter.
      • Sidhaye V.K.
      • Chau E.
      • Breysse P.N.
      • King L.S.
      Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions.
      These examples demonstrate that septin-dependent stabilization of epithelial and endothelial barriers could serve as a protective mechanism limiting immune cell exposure to environmental pathogens during tissue inflammation.

      Tissue Fibrosis

      Limited evidence, primarily derived from the liver and kidney, implicates the septin cytoskeleton in the regulation of aberrant tissue repair and fibrosis (Table 1). The only comprehensive characterization of septin expression in fibrotic tissues was performed in a mouse model of kidney fibrosis.
      • Neubauer K.
      • Neubauer B.
      • Seidl M.
      • Zieger B.
      Characterization of septin expression in normal and fibrotic kidneys.
      A gene expression analysis for different septins (SEPT1 and SEPT4 through SEPT11) demonstrates a significant up-regulation of all septin transcripts in the fibrotic kidney compared with controls. Immunohistologic experiments detect SEPT7 and SEPT8 protein up-regulation primarily in the tubulointerstitial region of the fibrotic kidney. Myofibroblasts are considered the chief profibrotic cell type across organs. Interestingly, septins were shown to significantly colocalize with the myofibroblast marker α-smooth muscle actin in the diseased kidneys.
      • Neubauer K.
      • Neubauer B.
      • Seidl M.
      • Zieger B.
      Characterization of septin expression in normal and fibrotic kidneys.
      SEPT4 and SEPT6 were also found up-regulated in different rodent models of liver fibrosis, where they were associated with hepatic stellate cells (HSC).
      • Fan Y.
      • Du Z.
      • Steib C.J.
      • Ding Q.
      • Lu P.
      • Tian D.
      • Liu M.
      Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism.
      ,
      • Duan Y.N.
      • Qian H.Y.
      • Qin Y.W.
      • Zhu D.D.
      • He X.X.
      • Zhou Q.
      • Yang Y.N.
      • Bao J.
      • Feng J.R.
      • Sun W.
      • Chen J.L.
      Dynamics of Sept4 expression in fibrotic livers of mice infected with Schistosoma japonicum.
      However, given a recent report that shows down-regulation of SEPT9 expression in carbon tetrachloride–induced liver fibrosis, septin expression could be a subject of more complex regulation in fibrotic tissues.
      • Wu Y.
      • Bu F.
      • Yu H.
      • Li W.
      • Huang C.
      • Meng X.
      • Zhang L.
      • Ma T.
      • Li J.
      Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis.
      Functional effects of selected septins on fibrogenesis were examined in a limited number of studies that utilized knockout mice models and adenovirus-mediated manipulation of septin expression in vivo. Mice with total knockout of SEPT4 display exaggerated hepatic fibrosis in three different experimental models (carbon tetrachloride, and cholestasis- and steatohepatitis-induced fibrosis).
      • Iwaisako K.
      • Hatano E.
      • Taura K.
      • Nakajima A.
      • Tada M.
      • Seo S.
      • Tamaki N.
      • Sato F.
      • Ikai I.
      • Uemoto S.
      • Kinoshita M.
      Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells.
      These profibrotic effects of SEPT4 deletion are linked to the increased activation and collagen-producing ability of HSC, the major myofibroblast precursor cell type in the liver. Supporting this loss of function data, adenoviral-mediated overexpression of SEPT4 suppresses hepatic fibrosis induced by Schistosoma japonicum infection in mice.
      • He X.
      • Bao J.
      • Chen J.
      • Sun X.
      • Wang J.
      • Zhu D.
      • Song K.
      • Peng W.
      • Xu T.
      • Duan Y.
      Adenovirus-mediated over-expression of Septin4 ameliorates hepatic fibrosis in mouse livers infected with Schistosoma japonicum.
      Antifibrotic effects of SEPT4 overexpression are associated with inhibition of HSC activity and their increased apoptosis. It is noteworthy that SEPT4 was shown to be a potent regulator of spontaneous and TGF-β–induced apoptosis in different tissues.
      • Larisch S.
      • Yi Y.
      • Lotan R.
      • Kerner H.
      • Eimerl S.
      • Tony Parks W.
      • Gottfried Y.
      • Birkey Reffey S.
      • de Caestecker M.P.
      • Danielpour D.
      • Book-Melamed N.
      • Timberg R.
      • Duckett C.S.
      • Lechleider R.J.
      • Steller H.
      • Orly J.
      • Kim S.J.
      • Roberts A.B.
      A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.
      ,
      • Koren E.
      • Yosefzon Y.
      • Ankawa R.
      • Soteriou D.
      • Jacob A.
      • Nevelsky A.
      • Ben-Yosef R.
      • Bar-Sela G.
      • Fuchs Y.
      ARTS mediates apoptosis and regeneration of the intestinal stem cell niche.
      In contrast to the reported antifibrotic functions of SEPT4, a recent study describes a profibrotic activity of SEPT6.
      • Fan Y.
      • Du Z.
      • Steib C.J.
      • Ding Q.
      • Lu P.
      • Tian D.
      • Liu M.
      Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism.
      Indeed, shRNA-mediated depletion of SEPT6 in vivo attenuates thioacetamide-induced hepatic fibrosis in rats by inhibiting HSC activation and decreasing the excessive extracellular matrix deposition seen in fibrosis.
      • Fan Y.
      • Du Z.
      • Steib C.J.
      • Ding Q.
      • Lu P.
      • Tian D.
      • Liu M.
      Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism.
      Finally, SEPT8-null mice do not show any differences in the development of kidney fibrosis as compared with wild-type controls, thereby suggesting dispensability of SEPT8 in this disease model.
      • Neubauer K.
      • Neubauer B.
      • Seidl M.
      • Zieger B.
      Characterization of septin expression in normal and fibrotic kidneys.
      At present, it is unclear whether the conflicting evidence reflects peculiar roles of different members of the septin family in fibrosis, or tissue-specific effects of the septin cytoskeleton on fibrogenesis. In addition, a temporal role of the septin cytoskeleton in early versus late tissue damage has not been evaluated yet.
      On a cellular level, septin-dependent regulation of tissue fibrosis is likely linked to the central profibrotic signaling pathway involving TGF-β. TGF-β is known to modulate septin expression and localization by up-regulating SEPT6
      • Fan Y.
      • Du Z.
      • Steib C.J.
      • Ding Q.
      • Lu P.
      • Tian D.
      • Liu M.
      Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism.
      ,
      • Simi A.K.
      • Anlaş A.A.
      • Stallings-Mann M.
      • Zhang S.
      • Hsia T.
      • Cichon M.
      • Radisky D.C.
      • Nelson C.M.
      A soft microenvironment protects from failure of midbody abscission and multinucleation downstream of the EMT-promoting transcription factor Snail.
      and down-regulating SEPT9 levels in the liver,
      • Wu Y.
      • Bu F.
      • Yu H.
      • Li W.
      • Huang C.
      • Meng X.
      • Zhang L.
      • Ma T.
      • Li J.
      Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis.
      as well as triggering nuclear translocation of SEPT4/ARTS in epithelial cells.
      • Larisch S.
      • Yi Y.
      • Lotan R.
      • Kerner H.
      • Eimerl S.
      • Tony Parks W.
      • Gottfried Y.
      • Birkey Reffey S.
      • de Caestecker M.P.
      • Danielpour D.
      • Book-Melamed N.
      • Timberg R.
      • Duckett C.S.
      • Lechleider R.J.
      • Steller H.
      • Orly J.
      • Kim S.J.
      • Roberts A.B.
      A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.
      Septins themselves could act as positive regulators of TGF-β signaling by stimulating expression of this growth factor and promoting TGF-β–driven Smad signaling, as was shown for SEPT6 and SEPT9 actions in HSC
      • Fan Y.
      • Du Z.
      • Steib C.J.
      • Ding Q.
      • Lu P.
      • Tian D.
      • Liu M.
      Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism.
      and glioma cells,
      • Zhang G.
      • Feng W.
      • Wu J.
      Down-regulation of SEPT9 inhibits glioma progression through suppressing TGF-beta-induced epithelial-mesenchymal transition (EMT).
      respectively. These data indicate that the septin cytoskeleton could be part of an important fibrogenic positive feedback loop mechanism involving TGF-β–induced up-regulation of septins, which in turn triggers further increase in TGF-β level and activity. Septins modulate other signaling pathways important for fibrogenesis in HSC. For example, SEPT6 up-regulates the activity of all three major MAP kinases: ERK, JNK, and p38,
      • Fan Y.
      • Du Z.
      • Steib C.J.
      • Ding Q.
      • Lu P.
      • Tian D.
      • Liu M.
      Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism.
      all of which have been implicated in organ fibrosis.
      • Ma F.Y.
      • Sachchithananthan M.
      • Flanc R.S.
      • Nikolic-Paterson D.J.
      Mitogen activated protein kinases in renal fibrosis.
      Furthermore, SEPT4 can limit HSC activation by stimulating expression of a Wnt antagonist, Dickkopf2, thereby inhibiting the canonical Wnt signaling.
      • Yanagida A.
      • Iwaisako K.
      • Hatano E.
      • Taura K.
      • Sato F.
      • Narita M.
      • Nagata H.
      • Asechi H.
      • Uemoto S.
      • Kinoshita M.
      Downregulation of the Wnt antagonist Dkk2 links the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells.

      The Septin Cytoskeleton as a Potential Target for Therapeutic Interventions

      Emerging functions of the septin cytoskeleton in regulating various aspects of the immune response and tissue remodeling during inflammation and fibrosis raise the important question of whether septins could be successfully targeted to develop novel anti-inflammatory and antifibrotic therapies. In general, functional activity of different cytoskeletal structures such as actin filaments and microtubules could be modulated by cell-permeable small molecules that cause either stabilization or disassembly of targeted cytoskeletal structures. The feasibility of clinical application of such compounds is illustrated by the successful use of microtubule-stabilizing taxane class drugs as anticancer agents. However, pharmacologic modulation of the septin cytoskeleton, while possible, remains at the very early stage of exploration. The experimental toolbox of septin-modulating compounds is very narrow with only one small molecule, forchlorfenuron (FCF), being extensively used to target the septin cytoskeleton in different experimental systems.
      • Heasley L.R.
      • McMurray M.A.
      Small molecule perturbations of septins.
      FCF was shown to block septin filament turnover, resulting in accumulation of thick septin bundles and aggregates.
      • Hu Q.
      • Nelson W.J.
      • Spiliotis E.T.
      Forchlorfenuron alters mammalian septin assembly, organization, and dynamics.
      Interestingly, such FCF-induced stabilization of the septin cytoskeleton mimics functional effects of the depletion of key septin paralogs by inhibiting cell division, migration, vesicle trafficking, calcium entry, and cell–cell adhesions.
      • Marcus E.A.
      • Tokhtaeva E.
      • Turdikulova S.
      • Capri J.
      • Whitelegge J.P.
      • Scott D.R.
      • Sachs G.
      • Berditchevski F.
      • Vagin O.
      Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells.
      ,
      • Tokhtaeva E.
      • Capri J.
      • Marcus E.A.
      • Whitelegge J.P.
      • Khuzakhmetova V.
      • Bukharaeva E.
      • Deiss-Yehiely N.
      • Dada L.A.
      • Sachs G.
      • Fernandez-Salas E.
      • Vagin O.
      Septin dynamics are essential for exocytosis.
      ,
      • Zhang N.
      • Liu L.
      • Fan N.
      • Zhang Q.
      • Wang W.
      • Zheng M.
      • Ma L.
      • Li Y.
      • Shi L.
      The requirement of SEPT2 and SEPT7 for migration and invasion in human breast cancer via MEK/ERK activation.
      ,
      • Sharma S.
      • Quintana A.
      • Findlay G.M.
      • Mettlen M.
      • Baust B.
      • Jain M.
      • Nilsson R.
      • Rao A.
      • Hogan P.G.
      An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry.
      ,
      • Sidhaye V.K.
      • Chau E.
      • Breysse P.N.
      • King L.S.
      Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions.
      ,
      • Hu Q.
      • Nelson W.J.
      • Spiliotis E.T.
      Forchlorfenuron alters mammalian septin assembly, organization, and dynamics.
      Despite diverse effects on cell function, FCF itself may not be suitable for clinical use in its current form. It has a relatively low affinity for septin filaments and hence is only active at high, submillimolar concentrations. Furthermore, possible off-target effects and animal tissue toxicity of FCF have been reported.
      • Sun L.
      • Cao X.
      • Lechuga S.
      • Feygin A.
      • Naydenov N.G.
      • Ivanov A.I.
      A septin cytoskeleton-targeting small molecule, forchlorfenuron, inhibits epithelial migration via septin-independent perturbation of cellular signaling.
      ,
      • Heasley L.R.
      • McMurray M.A.
      Small molecule perturbations of septins.
      ,
      • Blum W.
      • Henzi T.
      • Pecze L.
      • Diep K.L.
      • Bochet C.G.
      • Schwaller B.
      The phytohormone forchlorfenuron decreases viability and proliferation of malignant mesothelioma cells in vitro and in vivo.
      Nevertheless, studies utilizing FCF have laid the ground for the development of next-generation septin inhibitors. We expect that these inhibitors will be first developed as anticancer drugs, given the substantial body of evidence about mutations or altered expression of different septin paralogs being associated with tumorigenesis.
      • Angelis D.
      • Spiliotis E.T.
      Septin mutations in human cancers.
      Indeed, two recent studies report synthesis of different chemical derivatives of FCF and their effects on cancer cells.
      • Blum W.
      • Henzi T.
      • Pecze L.
      • Diep K.L.
      • Bochet C.G.
      • Schwaller B.
      The phytohormone forchlorfenuron decreases viability and proliferation of malignant mesothelioma cells in vitro and in vivo.
      ,
      • Kim K.K.
      • Singh R.K.
      • Khazan N.
      • Kodza A.
      • Singh N.A.
      • Jones A.
      • Sivagnanalingam U.
      • Towner M.
      • Itamochi H.
      • Turner R.
      • Moore R.G.
      Development of potent forchlorfenuron analogs and their cytotoxic effect in cancer cell lines.
      While one study characterizes cytotoxic effects of FCF derivatives in malignant mesothelioma cells, 
      • Blum W.
      • Henzi T.
      • Pecze L.
      • Diep K.L.
      • Bochet C.G.
      • Schwaller B.
      The phytohormone forchlorfenuron decreases viability and proliferation of malignant mesothelioma cells in vitro and in vivo.
      the other compares effects of FCF and its analogs on viability of ovarian and endometrial cancer cells.
      • Kim K.K.
      • Singh R.K.
      • Khazan N.
      • Kodza A.
      • Singh N.A.
      • Jones A.
      • Sivagnanalingam U.
      • Towner M.
      • Itamochi H.
      • Turner R.
      • Moore R.G.
      Development of potent forchlorfenuron analogs and their cytotoxic effect in cancer cell lines.
      Not much is known about the possibility of pharmacologic inhibition of the septin cytoskeleton during inflammation and tissue fibrosis. Further studies are required to examine potential utilization of FCF and its derivatives for the development of novel anti-inflammatory and antifibrotic therapies.

      Conclusion

      The septin cytoskeleton represents a critical component of cellular architecture that is known to mediate a variety of housekeeping and specialized functions. Most known for their roles in normal tissue development and homeostasis, septins are increasingly recognized as important contributors to human diseases. A significant body of literature links the altered expression and mutations of different septins with the development of neurological diseases and cancer. Much less is known about the role of the septin cytoskeleton in regulating tissue inflammation and fibrosis. As demonstrated in this review article, exciting recent developments in this field include discovering the roles of septins in the regulation of host interactions with bacterial and viral pathogens, modulation of lymphocytes differentiation, and profibrotic signaling (Table 1 and Figure 2). However, a number of important questions remain to be answered. For example, it is crucial to understand whether, as part of the same cytockeletal structure, different septins similarly regulate inflammatory and fibrotic responses, or whether members of the septin protein family have unique functional roles. It would be important to examine how septins regulate signaling by pattern recognition receptors that sense different pathogens, as well as signaling by different inflammatory cytokines and growth factors. Given the known roles of septins in the regulation of vesicle trafficking and the Golgi, it should be a research priority to determine whether the septin cytoskeleton controls secretion of different inflammatory factors by activated immune cells and regulates deposition of the extracellular matrix in fibrotic tissues. There is obvious need for extensive in vivo studies involving mouse models with tissue-specific knockout of different septins. From a therapeutic standpoint, it is critical to understand whether the septin cytoskeleton could be a druggable target during inflammation and tissue fibrosis, and to develop specific pharmacologic modulators of septin cytoskeletal assembly and dynamics. We are still at the very beginning of the exploration in this exciting and potentially fruitful research field, and future studies will pave the way for the modulation of septins to treat human inflammatory and fibrotic diseases.

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