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

doi:10.1073/pnas.0707025105

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

*The Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine,
Departments of ^§Pharmacology,
^‖Medicine, and
**Cell Biology, and
^¶New York University Cancer Institute, New York University School of Medicine, New York, NY 10016; and
^†Department of Biochemistry, Rappaport Institute for Research in the Medical Sciences, Technion–Israel Institute of Technology, 1 Efron Street, Bat–Galim, Haifa 31096, Israel

Edited by Arthur Horwich, Yale University School of Medicine, New Haven, CT, and approved March 11, 2008 (received for review August 10, 2007)

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.

Footnotes

^‡To whom correspondence may be addressed. E-mail: stanhill{at}tx.technion.ac.il
^††To whom correspondence may be addressed at:
New York University School of Medicine, Skirball Institute 3 Lab-10, 540 First Avenue, New York, NY 10016.
E-mail: ron{at}saturn.med.nyu.edu
Author contributions: C.Y. and A.S. contributed equally to this work; C.Y., A.S., and D.R. designed research; C.Y., A.S., Y.Y., Y.Z., C.-F.X., and A.M. performed research; C.M.H., C.-F.X., T.A.N., A.M., and M.R.P. contributed new reagents/analytic tools; C.Y., A.S., C.-F.X., T.A.N., A.M., M.R.P., and D.R. analyzed data; and C.Y., A.S., and D.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0707025105/DCSupplemental.