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Originally published in Science Express on 16 April 2009
Science 29 May 2009:
Vol. 324. no. 5931, pp. 1196 - 1198
DOI: 10.1126/science.1173507
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Reports

Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans

Ranjana Mehta,1,* Katherine A. Steinkraus,1,* George L. Sutphin,2 Fresnida J. Ramos,1 Lara S. Shamieh,1 Alexander Huh,1 Christina Davis,1 Devon Chandler-Brown,1 Matt Kaeberlein1,{dagger}

The Caenorhabditis elegans von Hippel–Lindau tumor suppressor homolog VHL-1 is a cullin E3 ubiquitin ligase that negatively regulates the hypoxic response by promoting ubiquitination and degradation of the hypoxic response transcription factor HIF-1. Here, we report that loss of VHL-1 significantly increased life span and enhanced resistance to polyglutamine and β-amyloid toxicity. Deletion of HIF-1 was epistatic to VHL-1, indicating that HIF-1 acts downstream of VHL-1 to modulate aging and proteotoxicity. VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.

1 Department of Pathology, University of Washington, Seattle, WA 98195, USA.
2 Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kaeber{at}u.washington.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Two Distinct Roles for EGL-9 in the Regulation of HIF-1-Mediated Gene Expression in Caenorhabditis elegans.
Z. Shao, Y. Zhang, and J. A. Powell-Coffman (2009)
Genetics 183, 821-829
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