Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP.

Authors:
Eszter Zavodszky
Eszter Zavodszky
Addenbrooke's Hospital
United Kingdom
Sokol V Todi
Sokol V Todi
Wayne State University School of Medicine
Srikanth Patury
Srikanth Patury
University of Michigan
United States
Ping Xu
Ping Xu
State Key Laboratory of Proteomics
China
Edgardo Rodriguez-Lebron
Edgardo Rodriguez-Lebron
University of Iowa
United States
John Konen
John Konen
University of Michigan
United States

Mol Cell 2011 Aug;43(4):599-612

Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

The mechanisms by which ubiquitin ligases are regulated remain poorly understood. Here we describe a series of molecular events that coordinately regulate CHIP, a neuroprotective E3 implicated in protein quality control. Through their opposing activities, the initiator E2, Ube2w, and the specialized deubiquitinating enzyme (DUB), ataxin-3, participate in initiating, regulating, and terminating the CHIP ubiquitination cycle. Monoubiquitination of CHIP by Ube2w stabilizes the interaction between CHIP and ataxin-3, which through its DUB activity limits the length of chains attached to CHIP substrates. Upon completion of substrate ubiquitination, ataxin-3 deubiquitinates CHIP, effectively terminating the reaction. Our results suggest that functional pairing of E3s with ataxin-3 or similar DUBs represents an important point of regulation in ubiquitin-dependent protein quality control. In addition, the results shed light on disease pathogenesis in SCA3, a neurodegenerative disorder caused by polyglutamine expansion in ataxin-3.
PDF Download - Full Text Link
( Please be advised that this article is hosted on an external website not affiliated with PubFacts.com)
Source Status
http://dx.doi.org/10.1016/j.molcel.2011.05.036DOI ListingPossible
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166620PMCFound
August 2011
6 Reads

Similar Publications

Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo.

J Biol Chem 2013 Nov 8;288(48):34460-9. Epub 2013 Oct 8.

From the Departments of Pharmacology and Neurology and.

Deubiquitinases (DUBs) are proteases that regulate various cellular processes by controlling protein ubiquitination. Cell-based studies indicate that the regulation of the activity of DUBs is important for homeostasis and is achieved by multiple mechanisms, including through their own ubiquitination. However, the physiological significance of the ubiquitination of DUBs to their functions in vivo is unclear. Read More

View Article
November 2013

The role of deubiquitinating enzymes in apoptosis.

Cell Mol Life Sci 2011 Jan 21;68(1):15-26. Epub 2010 Aug 21.

Department of Biomedical Science, CHA General Hospital, CHA University, 606-16 Yeoksam 1-Dong, Gangnam-Gu, Seoul, 135-081, Republic of Korea.

It has become apparent that ubiquitination plays a critical role in cell survival and cell death. In addition, deubiquitinating enzymes (DUBs) have been determined to be highly important regulators of these processes. Cells can be subjected to various stresses and respond in a variety of different ways ranging from activation of survival pathways to the promotion of cell death, which eventually eliminates damaged cells. Read More

View Article
January 2011

The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability.

Hum Mol Genet 2011 Jan 11;20(1):141-54. Epub 2010 Oct 11.

Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3. Interestingly, MJD can present clinically with features of Parkinsonism. In this study, we identify parkin, an E3 ubiquitin-ligase responsible for a common familial form of Parkinson's disease, as a novel ataxin-3 binding partner. Read More

View Article
January 2011

In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis.

Neurobiol Dis 2009 Mar 8;33(3):342-53. Epub 2008 Nov 8.

Graduate Program in Neuroscience and Medical Scientist Training Program, University of Iowa, 2206 MERF, Iowa City, IA 52242, USA.

Perturbations in neuronal protein homeostasis likely contribute to disease pathogenesis in polyglutamine (polyQ) neurodegenerative disorders. Here we provide evidence that the co-chaperone and ubiquitin ligase, CHIP (C-terminus of Hsp70-interacting protein), is a central component to the homeostatic mechanisms countering toxic polyQ proteins in the brain. Genetic reduction or elimination of CHIP accelerates disease in transgenic mice expressing polyQ-expanded ataxin-3, the disease protein in Spinocerebellar Ataxia Type 3 (SCA3). Read More

View Article
March 2009