title: Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans.
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.
authors.affiliation: The Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine.
authors.forename: Chi
authors.initials: C
authors.lastname: Yun
authors.forename: Ariel
authors.initials: A
authors.lastname: Stanhill
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cole M
authors.initials: CM
authors.lastname: Haynes
authors.forename: Chong-Feng
authors.initials: CF
authors.lastname: Xu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.forename: Adam
authors.initials: A
authors.lastname: Mor
authors.forename: Mark R
authors.initials: MR
authors.lastname: Philips
authors.forename: David
authors.initials: D
authors.lastname: Ron
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D018053:Arsenites / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004777:Environment; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding; D016601:RNA-Binding Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D018053:Arsenites; D029742:Caenorhabditis elegans Proteins; D016601:RNA-Binding Proteins; C436043:Zfand2a protein, mouse; D046988:Proteasome Endopeptidase Complex; C015001:arsenite