Premium
Misfolded proteins inhibit proliferation and promote stress‐induced death in SV40‐transformed mammalian cells
Author(s) -
Arslan Mehmet Alper,
Chikina Maria,
Csermely Péter,
Sőti Csaba
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-186197
Subject(s) - aggresome , microbiology and biotechnology , proteotoxicity , proteasome , chaperone (clinical) , hsf1 , heat shock protein , protein aggregation , protein folding , unfolded protein response , proteostasis , biology , programmed cell death , heat shock , hsp70 , chemistry , biochemistry , apoptosis , endoplasmic reticulum , autophagy , medicine , pathology , gene
Protein misfolding is implicated in neurodegenerative diseases and occurs in aging. However, the contribution of the misfolded ensembles to toxicity remains largely unknown. Here we introduce 2 primate cell models of destabilized proteins devoid of specific cellular functions and interactors, as bona fide mis‐folded proteins, allowing us to isolate the gain‐of‐function of non‐native structures. Both GFP‐degron and a mutant chloramphenicol‐acetyltransferase fused to GFP (GFP‐Δ9CAT) form perinuclear aggregates, are degraded by the proteasome, and colocalize with and induce the chaperone Hsp70 (HSPA1A/B) in COS‐7 cells. We find that misfolded proteins neither significantly compromise chaperone‐mediated folding capacity nor induce cell death. However, they do induce growth arrest in cells that are unable to degrade them and promote stress‐induced death upon proteasome inhibition by MG‐132 and heat shock. Finally, we show that overexpression of all heat‐shock factor‐1 (HSF1) and Hsp70 proteins, as well as wild‐type and deacetylase‐deficient (H363Y) SIRT1, rescue survival upon stress, implying a noncatalytic action of SIRT1 in response to protein misfolding. Our study establishes a novel model and extends our knowledge on the mechanism of the function‐independent proteotoxicity of misfolded proteins in dividing cells.—Arslan, M. A., Chikina, M., Csermely, P., Sőti, C. Misfolded proteins inhibit proliferation and promote stress‐induced death in SV40‐transformed mammalian cells. FASEB J. 26, 766–777 (2012). www.fasebj.org