Misfolded proteins inhibit proliferation and promote stress-induced death in SV40-transformed mammalian cells

Mehmet Alper Arslan, Maria Chikina, P. Csermely, C. Söti

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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 misfolded proteins, allowing us to isolate the gain-offunction 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.

Original languageEnglish
Pages (from-to)766-777
Number of pages12
JournalFASEB Journal
Volume26
Issue number2
DOIs
Publication statusPublished - Feb 2012

Fingerprint

Cells
Proteins
Proteasome Endopeptidase Complex
Shock
Hot Temperature
Neurodegenerative diseases
Chloramphenicol O-Acetyltransferase
COS Cells
Cell death
Neurodegenerative Diseases
Primates
Toxicity
Cell Death
Aging of materials
Growth

Keywords

  • HSF1
  • Hsp70
  • Sirtuin

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Misfolded proteins inhibit proliferation and promote stress-induced death in SV40-transformed mammalian cells. / Arslan, Mehmet Alper; Chikina, Maria; Csermely, P.; Söti, C.

In: FASEB Journal, Vol. 26, No. 2, 02.2012, p. 766-777.

Research output: Contribution to journalArticle

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