A deubiquitinase negatively regulates retro-translocation of nonubiquitinated substrates

Background:The AAA-ATPase VCP/p97 and the deubiquitinase YOD1 are required in the endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins. Results: Three ERAD substrates (NHK-␣1〈⌻, NS1-kLC, and Tetherin) become cytosolically exposed independently of p97 and YOD1, whereas MHC-I␣-and CD4-induced retro-translocation requires them. Conclusion: VCP/p97 and YOD1 have distinct substrate-dependent activities in ERAD. Significance: We demonstrate two different levels of p97 and YOD1 requirements in ERAD.

Section: Discussionmentioning

confidence: 99%

“…YOD1 is a p97-associated deubiquitinylase shown recently to be a key player in ERAD (4,5,35,36). The dominant negative mutant YOD1(C160S) has been shown to stabilize ERAD substrates mostly in a non-ubiquitylated and glycosylated form.…”

mentioning

confidence: 99%

The VCP/p97 and YOD1 Proteins Have Different Substrate-dependent Activities in Endoplasmic Reticulum-associated Degradation (ERAD)

Sasset

Petris

Cesaratto

et al. 2015

“…The pelleted membranes were washed with 800 mM salt to remove any peripheral membraneassociated proteins. The minor pool of Hsp90, which is consistently detected in association with the membrane fraction of digitonin-permeabilized cells (17,37,55), was removed by this wash (Fig. 2A).…”

Section: Atp Hydrolysis By Hsp90 Is Required For Cta1mentioning

confidence: 99%

Co- and Post-translocation Roles for HSP90 in Cholera Intoxication

Burress

Taylor

Banerjee

et al. 2014

Background:The unfolded A1 subunit of cholera toxin (CT) enters the host cytosol by passing through a pore in the endoplasmic reticulum (ER) membrane. Results: ATP-dependent refolding of CTA1 by Hsp90 is sufficient for toxin export to the cytosol. Conclusion: Hsp90 couples CTA1 refolding with CTA1 extraction from the ER. Significance: This work provides a molecular basis for toxin translocation into the host cytosol.

“…OTU1 is known as a deubiquitinating enzyme as well as a substrate-processing factor of VCP that is required for the retrotranslocation of the ERAD pathway (13). It also plays a role in controlling ubiquitinated or unubiquitinated substrates in the ERAD pathway (14). However, the exact mechanisms are not yet well understood.…”

mentioning

confidence: 99%

Structural Basis for Ovarian Tumor Domain-containing Protein 1 (OTU1) Binding to p97/Valosin-containing Protein (VCP)

Kim

Cho

Song

et al. 2014

Background: Ovarian tumor domain-containing protein 1 (OTU1) acts as a deubiquitinating enzyme in the endoplasmic reticulum-associated degradation (ERAD) pathway by associating with valosin-containing protein (VCP). Results: One OTU1 binds to a VCP hexamer with a K D of 0.71 M. Conclusion:The 39 GYPP 42 (S3/S4) loop of OTU1 is critical for interaction with VCP. Significance: This is the first structural study of VCP and OTU1 complex.