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Molecular and Cellular Biology, June 2008, p. 4018-4025, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00296-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control{triangledown}

Jin-Na Min,1 Ryan A. Whaley,1 Norman E. Sharpless,2,3,4 Pamela Lockyer,1 Andrea L. Portbury,1 and Cam Patterson1,3,5,6*

Carolina Cardiovascular Biology Center,1 Lineberger Comprehensive Cancer Center,2 Departments of Medicine,3 Genetics,4 Cell and Developmental Biology,5 Pharmacology, University of North Carolina, Chapel Hill, North Carolina6

Received 21 February 2008/ Accepted 5 April 2008

During the course of biological aging, there is a gradual accumulation of damaged proteins and a concomitant functional decline in the protein degradation system. Protein quality control is normally ensured by the coordinated actions of molecular chaperones and the protein degradation system that collectively help to maintain protein homeostasis. The carboxyl terminus of Hsp70-interacting protein (CHIP), a ubiquitin ligase/cochaperone, participates in protein quality control by targeting a broad range of chaperone substrates for proteasome degradation via the ubiquitin-proteasome system, demonstrating a broad involvement of CHIP in maintaining cytoplasmic protein quality control. In the present study, we have investigated the influence that protein quality control exerts on the aging process by using CHIP–/– mice. CHIP deficiency in mice leads to a markedly reduced life span, along with accelerated age-related pathophysiological phenotypes. These features were accompanied by indications of accelerated cellular senescence and increased indices of oxidative stress. In addition, CHIP–/– mice exhibit a deregulation of protein quality control, as indicated by elevated levels of toxic oligomer proteins and a decline in proteasome activity. Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo.

* Corresponding author. Mailing address: Division of Cardiology and Carolina Cardiovascular Biology, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126. Phone: (919) 843-6477. Fax: (919) 966-1743. E-mail: cpatters{at}med.unc.edu

{triangledown} Published ahead of print on 14 April 2008.

Molecular and Cellular Biology, June 2008, p. 4018-4025, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.00296-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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