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(American Journal of Pathology. 2006;169:889-902.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051161

JAB1 Determines the Response of Rheumatoid Arthritis Synovial Fibroblasts to Tumor Necrosis Factor-

Jianhua Wang^*, Chuanyu Li^*, Yuelong Liu^*, Wan Mei, Shaohua Yu^*, Cunren Liu^*, Liming Zhang^*, Xu Cao, Robert P. Kimberly^*, William Grizzle and Huang-Ge Zhang^*

From the Department of Medicine,^* Division of Clinical Immunology and Rheumatology, and the Department of Pathology, University of Alabama at Birmingham, Birmingham; and the Birmingham Veterans Administration Medical Center, Birmingham, Alabama

Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)- stimulation. Here, we show that JAB1 is a critical regulator of the TNF--mediated anti-apo-ptosis pathways in RA FLSs. We found that knockdown of JAB1 using small interfering (si)RNA led to restoration of the TNF--induced apoptosis response, reduction of nuclear factor-B activity, delayed degradation of IB-, and inhibited phosphorylation of JNK. Analysis of the interactions of JAB1 by reciprocal co-immunoprecipitations and confocal microscopy revealed that JAB1 interacts with TNF receptor-associated-factor 2 (TRAF2). The generation of the anti-apoptotic signal on binding of TNF- to the TNF receptor (TNFR)1 has been shown to be associated with the recruitment of TRAF2 to the TNFR1 in a process that requires ubiquitination of TRAF2 with lysine-63-linked polyubiquitin chains. We found that TNF- stimulation of JAB1 siRNA-transfected RA FLSs failed to stimulate ubiquitination of TRAF2. Thus, we conclude that JAB1-regulated ubiquitination of TRAF2 is a novel mechanism whereby TNF- can induce anti-apoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-B and JNK in RA FLSs.

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