Endoplasmic reticulum-associated degradation (ERAD) is an essential quality 
control process whereby misfolded proteins are exported from the endoplasmic 
reticulum and degraded by the proteasome in the cytosol. The ATPase p97 acts as 
an essential component of this process by providing the force needed for 
retrotranslocation and by serving as a processing station for the substrate once 
in the cytosol. Proteins containing the ubiquitin regulatory X (UBX) 
ubiquitin-like domain function as adaptors for p97 through their direct binding 
with the amino terminus of the ATPase. We demonstrate that the UBX protein SAKS1 
is able to act as an adaptor for p97 that negatively modulates ERAD. This 
requires the ability of SAKS1 to bind both polyubiquitin and p97. Moreover, the 
association between SAKS1 and p97 is positively regulated by polyubiquitin 
binding of the UBX protein. SAKS1 also negatively impacts the p97-dependent 
processing required for degradation of a cytosolic, non-ERAD, substrate. We find 
SAKS1 is able to protect polyubiquitin from the activity of deubiquitinases, 
such as ataxin-3, that are necessary for efficient ERAD. Thus, SAKS1 inhibits 
protein degradation mediated by p97 complexes in the cytosol with a component of 
the mechanism being the ability to shield polyubiquitin chains from 
ubiquitin-processing factors.