CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control.
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.
Min
Jin-Na
JN
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599-7126, USA.
Whaley
Ryan A
RA
Sharpless
Norman E
NE
Lockyer
Pamela
P
Portbury
Andrea L
AL
Patterson
Cam
C
D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D016922:Cellular Senescence; D003593:Cytoplasm / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D008055:Lipids; D018832:Molecular Chaperones; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D010100:Oxygen