Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 19, Pages 7094-7099Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0707025105
Keywords
aging; chaperones; environmental toxins; protein degradation
Categories
Funding
- NCRR NIH HHS [RR017990] Funding Source: Medline
- NIDDK NIH HHS [F32 DK061179, F32-DK61179, R37 DK047119, DK47119, R01 DK047119] Funding Source: Medline
- NIEHS NIH HHS [ES08681, R01 ES008681] Funding Source: Medline
- NINDS NIH HHS [P30 NS050276, NS050276] Funding Source: Medline
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The burden of protein misfolding is believed to contribute to aging. However, the links between adaptations to conditions associated with protein misfolding and resistance to the time-dependent attrition of cellular function remain poorly understood. We report that worms lacking aip-1, a homologue of mammalian AIRAP (arsenic-inducible proteasomal 19S regulatory particle-associated protein), are not only impaired in their ability to resist exposure to arsenite but also exhibit shortened lifespan and hypersensitivity to misfolding-prone proteins under normal laboratory conditions. Mammals have a second, constitutively expressed AIRAP-like gene (AIRAPL) that also encodes a proteasome-interacting protein, which shares with AIRAP the property of enhancing peptide accessibility to the proteasome's active site. Genetic rescue experiments suggest that features common to the constitutively expressed worm AIP-1 and mammalian AIRAPL (but missing in the smaller, arsenite-inducible AIRAP) are important to lifespan extension. In worms, a single AIRAP-related protein links proteasomal adaptation to environmental stress with resistance to both proteotoxic insults and maintenance of animal life span under normal conditions.
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