Regulation of ubiquitin-proteasome system mediated degradation by cytosolic stress

Mol Biol Cell. 2007 Nov;18(11):4279-91. doi: 10.1091/mbc.e07-05-0487. Epub 2007 Aug 15.

Abstract

ER-associated, ubiquitin-proteasome system (UPS)-mediated degradation of the wild-type (WT) gap junction protein connexin32 (Cx32) is inhibited by mild forms of cytosolic stress at a step before its dislocation into the cytosol. We show that the same conditions (a 30-min, 42 degrees C heat shock or oxidative stress induced by arsenite) also reduce the endoplasmic reticulum (ER)-associated turnover of disease-causing mutants of Cx32 and the cystic fibrosis transmembrane conductance regulator (CFTR), as well as that of WT CFTR and unassembled Ig light chain. Stress-stabilized WT Cx32 and CFTR, but not the mutant/unassembled proteins examined, could traverse the secretory pathway. Heat shock also slowed the otherwise rapid UPS-mediated turnover of the cytosolic proteins myoD and GFPu, but not the degradation of an ubiquitination-independent construct (GFP-ODC) closely related to the latter. Analysis of mutant Cx32 from cells exposed to proteasome inhibitors and/or cytosolic stress indicated that stress reduces degradation at the level of substrate polyubiquitination. These findings reveal a new link between the cytosolic stress-induced heat shock response, ER-associated degradation, and polyubiquitination. Stress-denatured proteins may titer a limiting component of the ubiquitination machinery away from pre-existing UPS substrates, thereby sparing the latter from degradation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Connexins / genetics
  • Connexins / metabolism
  • Cricetinae
  • Cricetulus
  • Cytosol / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Glutamic Acid / genetics
  • Glutamic Acid / metabolism
  • Hot Temperature
  • Mutation / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Transport
  • Substrate Specificity
  • Ubiquitin / metabolism*

Substances

  • Connexins
  • Ubiquitin
  • Glutamic Acid
  • Proteasome Endopeptidase Complex