CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control
- 1 June 2008
- journal article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 28 (12), 4018-4025
- https://doi.org/10.1128/mcb.00296-08
Abstract
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.Keywords
This publication has 48 references indexed in Scilit:
- Senescence of renal cells: molecular basis and clinical implicationsNephrology Dialysis Transplantation, 2003
- Protein quality control: U-box-containing E3 ubiquitin ligases join the foldTrends in Biochemical Sciences, 2002
- Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataractNature Genetics, 2002
- Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot‐2 (mortalin)/mthsp70/Grp75FEBS Letters, 2002
- Molecular Chaperones in the Cytosol: from Nascent Chain to Folded ProteinScience, 2002
- Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesisNature, 2001
- Impairment of the Ubiquitin-Proteasome System by Protein AggregationScience, 2001
- Caretaker or undertaker? The role of the proteasome in agingMechanisms of Ageing and Development, 2001
- The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteinsNature, 2000
- Genome-wide study of aging and oxidative stress response inDrosophilamelanogasterProceedings of the National Academy of Sciences of the United States of America, 2000