Ubiquitin Chain Elongation Enzyme Ufd2 Regulates a Subset of Doa10 Substrates

Liu, Chang; Dyk, Dewald van; Xu, Ping; Choe, Vitnary; Pan, Haihui; Peng, Junmin; Andrews, Brenda; Rao, Hai

doi:10.1074/jbc.m110.110551

Cited by 21 publications

(30 citation statements)

References 36 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6b to d) and suggest that all cellular functions of Ufd2 depend on Cdc48 binding. This would imply that all Ufd2 substrates are also Cdc48 substrates, a prediction supported by a recent study characterizing novel Ufd2 substrates (40).…”

Section: Discussionsupporting

confidence: 49%

“…Interestingly, the ufd3-R541A,R669A mutant strain also exhibited intermediate degradation kinetics, suggesting either that the UFD phenotype of ⌬ufd3 is partially Cdc48 independent or, more likely, that some residual Cdc48 binding to Ufd3-R541A,R669A exists, perhaps bridged by the overexpressed UFD substrate. Finally, we analyzed the degradation kinetics of the recently characterized Ufd2-dependent bona fide ERAD substrate Pex29 (40) in the cdc48 mutant strains. In line with the results noted above, Pex29 was strongly stabilized in the cdc48-Y834E strain and moderately but significantly stabilized in the cdc48-Y834F strain (Fig.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cellular Functions of Ufd2 and Ufd3 in Proteasomal Protein Degradation Depend on Cdc48 Binding

Böhm

Lamberti

Fernández‐Sáiz

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

The chaperone-related AAA ATPase Cdc48 (p97/VCP in higher eukaryotes) segregates ubiquitylated proteins for subsequent degradation by the 26S proteasome or for nonproteolytic fates. The specific outcome of Cdc48 activity is controlled by the evolutionary conserved cofactors Ufd2 and Ufd3, which antagonistically regulate the substrates' ubiquitylation states. In contrast to the interaction of Ufd3 and Cdc48, the interaction between the ubiquitin chain elongating enzyme Ufd2 and Cdc48 has not been precisely mapped. Consequently, it is still unknown whether physiological functions of Ufd2 in fact require Cdc48 binding. Here, we show that Ufd2 binds to the C-terminal tail of Cdc48, unlike the human Ufd2 homologue E4B, which interacts with the N domain of p97. The binding sites for Ufd2 and Ufd3 on Cdc48 overlap and depend critically on the conserved residue Y834 but are not identical. Saccharomyces cerevisiae cdc48 mutants altered in residue Y834 or lacking the C-terminal tail are viable and exhibit normal growth. Importantly, however, loss of Ufd2 and Ufd3 binding in these mutants phenocopies defects of ⌬ufd2 and ⌬ufd3 mutants in the ubiquitin fusion degradation (UFD) and Ole1 fatty acid desaturase activation (OLE) pathways. These results indicate that key cellular functions of Ufd2 and Ufd3 in proteasomal protein degradation require their interaction with Cdc48.

show abstract

Section: Discussionsupporting

confidence: 49%

mentioning

confidence: 99%

Cellular Functions of Ufd2 and Ufd3 in Proteasomal Protein Degradation Depend on Cdc48 Binding

Böhm

Lamberti

Fernández‐Sáiz

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…S3). We previously demonstrated that accumulation of large amounts of substrates can cause toxicity in cells compromised for proteolysis (16). Indeed, Cdc13 overexpression led to growth retardation in vms1⌬ mutants (Fig.…”

Section: Vms1mentioning

confidence: 99%

The Cdc48 Protein and Its Cofactor Vms1 Are Involved in Cdc13 Protein Degradation

Baek

Cheng

Kim

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Vms1 is a recently isolated Cdc48 cofactor but has few degradation targets under normal growth conditions. Results: Vms1 and Cdc48 promote Cdc13 turnover, which involves both the proteasome and autophagy. Conclusion: Our study reveals novel functions of Vms1 and autophagy. Significance: Cdc13 may be the first ubiquitylated yeast protein subject to both degradation pathways under normal growth conditions.

show abstract

“…Ufd2p interacts with Cdc48p and Rad23p in the process of substrate delivery to the proteasome (28). It is intriguing that Ufd2p regulates turnover of only a subset of Doa10p substrates (33), and Hul5p has been found to be associated with the 19S proteasome (32,52,53). We determined the t1 ⁄ 2 , poly-ubiquitination of Pca1p, and formation of a complex between Pca1p and the proteasome in ufd2⌬ and hul5⌬ strains.…”

Section: Cdc48p Is Required For Complex Formation Between Pca1p and Tmentioning

confidence: 99%

“…E4 ubiquitin chain extension enzymes (e.g. Ufd2p and Hul5p) facilitate ERAD through poly-ubiquitination (10,32,33).…”

mentioning

confidence: 99%

Endoplasmic Reticulum-associated Degradation of Pca1p, a Polytopic Protein, via Interaction with the Proteasome at the Membrane

Smith

Adle

Zhao

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Endoplasmic reticulum-associated degradation (ERAD) plays a critical role in the destruction of terminally misfolded proteins at the secretory pathway. The system also regulates expression levels of several proteins such as Pca1p, a cadmium exporter in yeast. To gain better insight into the mechanisms underlying ERAD of Pca1p and other polytopic proteins by the proteasome in the cytosol, our study determined the roles for the molecular factors of ERAD in dislodging Pca1p from the endoplasmic reticulum (ER). Inactivation of the 20S proteasome leads to accumulation of ubiquitinated Pca1p in the ER membrane, suggesting a role for the proteasome in extraction of Pca1p from the ER. Pca1p formed a complex with the proteasome at the membrane in a Doa10p E3 ligase-dependent manner. Cdc48p is required for recruiting the proteasome to Pca1p. Although the Ufd2p E4 ubiquitin chain extension enzyme is involved in efficient degradation of Pca1p, Ufd2p-deficient cells did not affect the formation of a complex between Pca1p and the proteasome. Two other polytopic membrane proteins undergoing ERAD, Ste6*p and Hmg2p, also displayed the same outcomes observed for Pca1p. However, poly-ubiquitinated Cpy1*p, a luminal ERAD substrate, was detected in the cytosol independent of proteolytic activities of the proteasome. These results indicate that extraction and degradation of polytopic membrane proteins at the ER is a coupled event. This mechanism would relieve the cost of exposed hydrophobic domains in the cytosol during ERAD.

show abstract

Ubiquitin Chain Elongation Enzyme Ufd2 Regulates a Subset of Doa10 Substrates

Cited by 21 publications

References 36 publications

Cellular Functions of Ufd2 and Ufd3 in Proteasomal Protein Degradation Depend on Cdc48 Binding

Cellular Functions of Ufd2 and Ufd3 in Proteasomal Protein Degradation Depend on Cdc48 Binding

The Cdc48 Protein and Its Cofactor Vms1 Are Involved in Cdc13 Protein Degradation

Endoplasmic Reticulum-associated Degradation of Pca1p, a Polytopic Protein, via Interaction with the Proteasome at the Membrane

Contact Info

Product

Resources

About