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Vol. 18, Issue 11, 4279-4291, November 2007

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Regulation of Ubiquitin-Proteasome System–mediated Degradation by Cytosolic Stress

Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239

Submitted May 24, 2007; Revised July 13, 2007; Accepted August 8, 2007
Monitoring Editor: Jonathan Weissman

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°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.

Address correspondence to: Linda S. Musil (musill{at}OHSU.edu)

Abbreviations used: BFA, brefeldin A; CHX, cycloheximide; Cx32, connexin32; Cx43, connexin43; DTT, dithiothreitol; ERAD, ER-associated degradation; H/O stress, hyperthermic/oxidative stress; UPS, ubiquitin-proteasome system; WT, wild-type.

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