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Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans.

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.

Pubmed ID: 18467495 RIS Download

Mesh terms: Adaptation, Physiological | Animals | Arsenites | Caenorhabditis elegans | Caenorhabditis elegans Proteins | Cell Line | Endoplasmic Reticulum | Environment | Humans | Intracellular Membranes | Longevity | Mice | Phenotype | Proteasome Endopeptidase Complex | Protein Binding | Protein Folding | RNA-Binding Proteins | Sequence Homology, Amino Acid

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK047119
  • Agency: NCRR NIH HHS, Id: RR017990
  • Agency: NIEHS NIH HHS, Id: R01 ES008681
  • Agency: NIEHS NIH HHS, Id: ES08681
  • Agency: NIDDK NIH HHS, Id: R37 DK047119
  • Agency: NINDS NIH HHS, Id: P30 NS050276
  • Agency: NINDS NIH HHS, Id: NS050276
  • Agency: NIDDK NIH HHS, Id: F32 DK061179
  • Agency: NIDDK NIH HHS, Id: F32-DK61179
  • Agency: NIDDK NIH HHS, Id: DK47119

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