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(American Journal of Pathology. 2006;169:1939-1952.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060183

Role of Endocytic Inhibitory Drugs on Internalization of Amyloidogenic Light Chains by Cardiac Fibroblasts

Grace Fortes Monis*{dagger}, Christopher Schultz{dagger}, Ruiyi Ren{dagger}{ddagger}, Jeremy Eberhard{dagger}, Catherine Costello{dagger}{ddagger}, Lawreen Connors{dagger}{ddagger}, Martha Skinner{dagger}§ and Vickery Trinkaus-Randall{dagger}{ddagger}

From the Departments of Pathology,* Biochemistry,{ddagger} Ophthalmology, and Medicine,§ The Mass Spectrometry Resource 224 and the Amyloid Treatment and Research Program and Gerry Amyloid Research Laboratory,{dagger} Boston University School of Medicine, Boston, Massachusetts

Amyloidosis is a disease of protein misfolding that ultimately impairs organ function. Previously, we demonstrated that amyloidogenic light chains ({kappa}1, {lambda}6, and {lambda}3 subtypes), internalized by cardiac fibroblasts, enhanced sulfation of secreted glycosaminoglycans. In this study, we investigated the inter-nalization and cellular trafficking of urinary immunoglobulin light chains into cardiac fibroblasts. We demonstrate that these light chains have the ability to form annular rings in solution. Internalization was assessed by incubating cells in the presence of light chain conjugated to Oregon Green 488 followed by monitoring with live cell confocal imaging. The rate of light chain internalization was reduced by treatment with methyl-ß-cyclodextrin but not filipin. Amyloid light chain did co-localize with dextran-Texas Red. Once internalized, the light chains were detected in lysosomes and then secreted into the extracellular medium. The light chain detected in the cell lysate and medium possessed a lower hydrophobic species. Nocodazole, a microtubule inhibitor, did not disperse aggregates. In addition, internalization and retention of the light chain proteins was altered in the presence of the proteasomal inhibitor MG132. These results indicate that the cell internalizes light chain by a fluid phase endocytosis, which is then modified and ultimately compro-mises the cell.






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Copyright © 2006 by the American Society for Investigative Pathology.