Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 1321K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, Q. Articles by Ye, Y. Search for Related Content PubMed PubMed Citation Articles by Wang, Q. Articles by Ye, Y. Related Collections Related Article Social Bookmarking                            What's this?

Regulation of retrotranslocation by p97-associated deubiquitinating enzyme ataxin-3

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Correspondence to Yihong Ye: yihongy{at}mail.nih.gov

Misfolded proteins of the endoplasmic reticulum undergo retrotranslocation to enter the cytosol where they are degraded by the proteasome. Retrotranslocation of many substrates requires an ATPase complex consisting of the p97 ATPase and a dimeric cofactor, Ufd1-Npl4. We report that efficient elimination of misfolded ER proteins also involves ataxin-3 (atx3), a p97-associated deubiquitinating enzyme mutated in type-3 spinocerebellar ataxia. Overexpression of an atx3 mutant defective in deubiquitination inhibits the degradation of misfolded ER proteins and triggers ER stress. Misfolded polypeptides stabilized by mutant atx3 are accumulated in part as polyubiquitinated form, suggesting an involvement of its deubiquitinating activity in ER-associated protein degradation regulation. We demonstrate that atx3 transiently associates with the ER membrane via p97 and the recently identified Derlin–VIMP complex, and its release from the membrane appears to be governed by both the p97 ATPase cycle and its own deubiquitinating activity. We present evidence that atx3 may promote p97-associated deubiquitination to facilitate the transfer of polypeptides from p97 to the proteasome.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

Trimming ERAD

Rabiya S. Tuma
J. Cell Biol. 2006 174: 907b. [Full Text] [PDF]

This article has been cited by other articles:

• Ying, Z., Wang, H., Fan, H., Zhu, X., Zhou, J., Fei, E., Wang, G. (2009). Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. Hum Mol Genet 18: 4268-4281 [Abstract] [Full Text]  
• Wang, Q., Mora-Jensen, H., Weniger, M. A., Perez-Galan, P., Wolford, C., Hai, T., Ron, D., Chen, W., Trenkle, W., Wiestner, A., Ye, Y. (2009). ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. Proc. Natl. Acad. Sci. USA 106: 2200-2205 [Abstract] [Full Text]  
• Duennwald, M. L., Lindquist, S. (2008). Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity. Genes Dev. 22: 3308-3319 [Abstract] [Full Text]  
• Winborn, B. J., Travis, S. M., Todi, S. V., Scaglione, K. M., Xu, P., Williams, A. J., Cohen, R. E., Peng, J., Paulson, H. L. (2008). The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains. J. Biol. Chem. 283: 26436-26443 [Abstract] [Full Text]  
• Wang, Q., Li, L., Ye, Y. (2008). Inhibition of p97-dependent Protein Degradation by Eeyarestatin I. J. Biol. Chem. 283: 7445-7454 [Abstract] [Full Text]  
• Shapira, I., Charuvi, D., Elkabetz, Y., Hirschberg, K., Bar-Nun, S. (2007). Distinguishing between retention signals and degrons acting in ERAD. J. Cell Sci. 120: 4377-4387 [Abstract] [Full Text]  
• Huttunen, H. J., Guenette, S. Y., Peach, C., Greco, C., Xia, W., Kim, D. Y., Barren, C., Tanzi, R. E., Kovacs, D. M. (2007). HtrA2 Regulates beta-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation. J. Biol. Chem. 282: 28285-28295 [Abstract] [Full Text]  
• Baker, B. M., Tortorella, D. (2007). Dislocation of an Endoplasmic Reticulum Membrane Glycoprotein Involves the Formation of Partially Dislocated Ubiquitinated Polypeptides. J. Biol. Chem. 282: 26845-26856 [Abstract] [Full Text]  
• Yi, J. J., Ehlers, M. D. (2007). Emerging Roles for Ubiquitin and Protein Degradation in Neuronal Function. Pharmacol. Rev. 59: 14-39 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents