The UBX protein SAKS1 negatively regulates endoplasmic reticulum-associated degradation and p97-dependent degradation.
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.
Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853, USA. DPL36@cornell.edu
David P
DP
LaLonde
Anthony
A
Bretscher
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000067699:Ataxin-3; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012097:Repressor Proteins; D000074405:Valosin Containing Protein
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C504037:UBXN1 protein, human; D025821:Polyubiquitin; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein