Affordable Access

Role of endocytic inhibitory drugs on internalization of amyloidogenic light chains by cardiac fibroblasts.

Authors
  • Monis, Grace Fortes
  • Schultz, Christopher
  • Ren, Ruiyi
  • Eberhard, Jeremy
  • Costello, Catherine
  • Connors, Lawreen
  • Skinner, Martha
  • Trinkaus-Randall, Vickery
Type
Published Article
Journal
The American journal of pathology
Publication Date
Dec 01, 2006
Volume
169
Issue
6
Pages
1939–1952
Identifiers
PMID: 17148659
Source
Medline
License
Unknown

Abstract

Amyloidosis is a disease of protein misfolding that ultimately impairs organ function. Previously, we demonstrated that amyloidogenic light chains (kappa1, lambda6, and lambda3 subtypes), internalized by cardiac fibroblasts, enhanced sulfation of secreted glycosaminoglycans. In this study, we investigated the internalization 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-beta-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 compromises the cell.

Report this publication

Statistics

Seen <100 times