TY - JOUR
T1 - Cell damage in light chain amyloidosis fibril internalization, toxicity and cell-mediated seeding
AU - Marin-Argany, Marta
AU - Lin, Yi
AU - Misra, Pinaki
AU - Williams, Angela
AU - Wall, Jonathan S.
AU - Howell, Kyle G.
AU - Elsbernd, Laura R.
AU - McClure, Megan
AU - Ramirez-Alvarado, Marina
N1 - Funding Information:
This work was supported by National Institutes of Health Grants R01 GM071514 (to M. R.-A.) and R01 DK079984 (to J. S. W.) and by Dr. Morie Gertz, the Seidler Professorship, and the Mayo Foundation. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article contains supplemental Figs. S1-S3.
Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/9/16
Y1 - 2016/9/16
N2 - Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis.
AB - Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis.
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U2 - 10.1074/jbc.M116.736736
DO - 10.1074/jbc.M116.736736
M3 - Article
C2 - 27462073
AN - SCOPUS:84987841004
SN - 0021-9258
VL - 291
SP - 19813
EP - 19825
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 38
ER -