Roles of p97-associated deubiquitinases in protein quality control at the endoplasmic reticulum.
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 retrotranslocation- 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.
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Yanfen
Y
Liu
Yihong
Y
Ye
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D000067699:Ataxin-3; D018797:Cell Cycle Proteins / Q000378:metabolism; D010450:Endopeptidases; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; C545663:YOD1 protein, human; D013869:Thiolester Hydrolases; D010450:Endopeptidases; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D000251:Adenosine Triphosphatases; C404942:p97 ATPase; D000074405:Valosin Containing Protein