HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 11, 6783-6789, March 14, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/11/6783    most recent M709496200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wooten, M. W. Articles by Moscat, J. Search for Related Content PubMed PubMed Citation Articles by Wooten, M. W. Articles by Moscat, J. Social Bookmarking                      What's this?

Essential Role of Sequestosome 1/p62 in Regulating Accumulation of Lys⁶³-ubiquitinated Proteins^*

Marie W. Wooten¹, Thangiah Geetha, J. Ramesh Babu, M. Lamar Seibenhener, Junmin Peng, Nancy Cox^¶, Maria-T. Diaz-Meco^||, and Jorge Moscat^||

From the Department of Biological Sciences, Program in Cell and Molecular Biosciences, Auburn University, Auburn, Alabama 36849, the Alzheimer Disease Research Center, Emory University, Atlanta, Georgia 30322, the ^¶Scott Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849, and the ^||Department of Genome Science, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 45237

Sequestosome 1 (SQSTM1)/p62 is an interacting partner of the atypical protein kinase C / and serves as a scaffold for cell signaling and ubiquitin binding, which is critical for several cell functions in vivo such as osteoclastogenesis, adipogenesis, and T cell activation. Here we report that in neurons of p62^–/– mouse brain there is a detectable increase in ubiquitin staining paralleled by accumulation of insoluble ubiquitinated proteins. The absolute amount of each ubiquitin chain linkage measured by quantitative mass spectrometry demonstrated hyperaccumulation of Lys⁶³ chains in the insoluble fraction recovered from the brain of p62^–/– mice, which correlated with increased levels of Lys⁶³-ubiquitinated TrkA receptor. The increase in Lys⁶³ chains was attributed in part to diminished activity of the TRAF6-interacting the Lys⁶³-deubiquitinating enzyme (DUB), cylindromatosis tumor suppressor (CYLD). The interaction of CYLD with TRAF6 was dependent upon p62, thus defining a mechanism that accounts for decreased activity of CYLD in the absence of p62. These findings reveal that p62 serves as an adapter for the formation of this complex, thereby regulating the DUB activity of CYLD by TRAF6 interaction. Thus, p62 has a bifunctional role in regulation of an E3 ubiquitin-protein ligase, TRAF6, and a DUB, CYLD, to balance the turnover of Lys⁶³-polyubiquitinated proteins such as TrkA.

Received for publication, November 19, 2007 , and in revised form, December 31, 2007.

^* This work was supported by the National Institutes of Health Grant NS-33661 (to M. W. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 331 Funchess Hall, Auburn University, Auburn, AL 36849. Tel.: 334-844-9226; Fax: 334-844-5255; E-mail: wootemw{at}auburn.edu.

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

This article has been cited by other articles:

				R. Yoshimi, T.-H. Chang, H. Wang, T. Atsumi, H. C. Morse III, and K. Ozato Gene Disruption Study Reveals a Nonredundant Role for TRIM21/Ro52 in NF-{kappa}B-Dependent Cytokine Expression in Fibroblasts J. Immunol., June 15, 2009; 182(12): 7527 - 7538. [Abstract] [Full Text] [PDF]

				J. Y. Kim and K. Ozato The Sequestosome 1/p62 Attenuates Cytokine Gene Expression in Activated Macrophages by Inhibiting IFN Regulatory Factor 8 and TNF Receptor-Associated Factor 6/NF-{kappa}B Activity J. Immunol., February 15, 2009; 182(4): 2131 - 2140. [Abstract] [Full Text] [PDF]