期刊
CURRENT PROTEIN & PEPTIDE SCIENCE
卷 13, 期 5, 页码 436-446出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138920312802430608
关键词
p97/VCP/Cdc48; ERAD/retrotranslocation; deubiquitination; ataxin-3; YOD1; proteasome; ubiquitin; ER protein quality control
资金
- NIH intramural AIDS Targeted Antiviral Program (IATAP)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
To maintain protein homeostasis in the ER, an ER protein quality control system retains unfolded polypeptides and misassembled membrane proteins, allowing only properly folded proteins to exit the ER. Misfolded proteins held in the ER are retrotranslocated into the cytosol, ubiquitinated, and degraded by the proteasome through the ER-associated degradation pathway (ERAD). By timely eliminating misfolded proteins, the ERAD system alleviates cytotoxic stress imposed by protein misfolding. It is well established that ER-associated ubiquitin ligases play pivotal roles in ERAD by assembling ubiquitin conjugates on retrotranslocation substrates, which serve as degradation signals for the proteasome. Surprisingly, recent studies have revealed an equally important function for deubiquitinases (DUBs), enzymes that disassemble ubiquitin chains, in ERAD. Intriguingly, many ERAD specific DUBs are physically associated with the retrotrans-location-driving ATPase p97. Here we discuss the potential functions of p97-associated DUBs including ataxin-3 and YOD1. Our goal is to integrate the emerging evidence into models that may explain how protein quality control could benefit from deubiquitination, a process previously deemed destructive for proteasomal degradation.
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