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

Proc Natl Acad Sci U S A. 2008 May 13;105(19):7094-9. doi: 10.1073/pnas.0707025105. Epub 2008 May 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptation, Physiological* / drug effects
  • Animals
  • Arsenites / toxicity
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Line
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Environment*
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism
  • Longevity / drug effects
  • Longevity / physiology*
  • Mice
  • Phenotype
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding / drug effects
  • Protein Folding*
  • RNA-Binding Proteins / metabolism
  • Sequence Homology, Amino Acid

Substances

  • Arsenites
  • Caenorhabditis elegans Proteins
  • RNA-Binding Proteins
  • Zfand2a protein, mouse
  • Proteasome Endopeptidase Complex
  • arsenite