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Molecular and Cellular Biology, January 2009, p. 116-128, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.00829-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Critical Role for CHIP in the Aggresome Pathway {triangledown} ,{dagger}

Youbao Sha, Lavannya Pandit, Shenyan Zeng, and N. Tony Eissa*

Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Received 22 May 2008/ Returned for modification 21 July 2008/ Accepted 17 October 2008

Recent evidence suggests that aggresome formation is a physiologic stress response not limited to misfolded proteins. That stress response, termed "physiologic aggresome," is exemplified by aggresome formation of inducible nitric oxide synthase (iNOS), an important host defense protein. CHIP (carboxy terminus of Hsp70-interacting protein) is a highly conserved protein that has been shown to mediate substrate ubiquitination and degradation by the proteasome. In this study, we show that CHIP has a previously unexpected critical role in the aggresome pathway. CHIP interacts with iNOS and promotes its ubiquitination and degradation by the proteasome as well as its sequestration to the aggresome. CHIP-mediated iNOS targeting to the proteasome sequentially precedes CHIP-mediated iNOS sequestration to the aggresome. CHIP is required for iNOS preaggresome structures to form a mature aggresome. Furthermore, CHIP is required for targeting the mutant form of cystic fibrosis transconductance regulator (CFTR{Delta}F508) to the aggresome. Importantly, the ubiquitin ligase function of CHIP is required in targeting preaggresomal structures to the aggresome by promoting an iNOS interaction with histone deacetylase 6, which serves as an adaptor between ubiquitinated proteins and the dynein motor. This study reveals a critical role for CHIP in the aggresome pathway.

* Corresponding author. Mailing address: Baylor College of Medicine, One Baylor Plaza, BCM 285 Suite 535E, Houston, TX 77030. Phone: (713) 798-3657. Fax: (713) 798-2050. E-mail: teissa{at}bcm.edu

{triangledown} Published ahead of print on 27 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2009, p. 116-128, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.00829-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Pandit, L., Kolodziejska, K. E., Zeng, S., Eissa, N. T. (2009). The physiologic aggresome mediates cellular inactivation of iNOS. Proc. Natl. Acad. Sci. USA 106: 1211-1215 [Abstract] [Full Text]  


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