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.
Yun
Chi
C
The Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine.
Stanhill
Ariel
A
Yang
Yun
Y
Zhang
Yuhong
Y
Haynes
Cole M
CM
Xu
Chong-Feng
CF
Neubert
Thomas A
TA
Mor
Adam
A
Philips
Mark R
MR
Ron
David
D
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
D018053:Arsenites; D029742:Caenorhabditis elegans Proteins; D016601:RNA-Binding Proteins; C436043:Zfand2a protein, mouse; D046988:Proteasome Endopeptidase Complex; C015001:arsenite