OLA1 protects cells in heat shock by stabilizing HSP70

R. F. Mao, V. Rubio, H. Chen, L. Bai, O. C. Mansour, Z. Z. Shi

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The heat-shock response is an evolutionarily conserved cellular defense mechanism against environmental stresses, characterized by the rapid synthesis of heat-shock proteins (HSPs). HSP70, a highly inducible molecular chaperone, assists in refolding or clearance of damaged proteins, thereby having a central role in maintaining intracellular homeostasis and thermotolerance. To date, induction of HSP70 expression has been described extensively at the transcriptional level. However, post-translational regulation of HSP70, such as protein stability, is only partially understood. In this study, we investigated the role of OLA1 (Obg-like ATPase 1), a previously uncharacterized cytosolic ATPase, in regulating the turnover of HSP70. Downregulation of OLA1 in mammalian cells by either RNAi or targeted gene disruption results in reduced steady-state levels of HSP70, impaired HSP70 induction by heat, and functionally, increased cellular sensitivity to heat shock. Conversely, overexpression of OLA1 correlates with elevated HSP70 protein levels and improved thermal resistance. Proteinprotein interaction assays demonstrated that binding of OLA1 to the HSP70 carboxyl terminus variable domain hinders the recruitment of CHIP (C-terminus of Hsp70-binding protein), an E3 ubiquitin ligase for HSP70, and thus prevents HSP70 from the CHIPmediated ubiquitination. These findings suggest a novel molecular mechanism by which OLA1 stabilizes HSP70, leading to upregulation of HSP70 as well as increased survival during heat shock.

Original languageEnglish (US)
JournalCell Death and Disease
Volume4
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • CHIP
  • Heat-shock response
  • Homeostasis
  • HSP70
  • OLA1

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

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