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.