Proteasomal regulation of the hypoxic response modulates aging in C. elegans.
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 beta-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.
Mehta
Ranjana
R
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
Steinkraus
Katherine A
KA
Sutphin
George L
GL
Ramos
Fresnida J
FJ
Shamieh
Lara S
LS
Huh
Alexander
A
Davis
Christina
C
Chandler-Brown
Devon
D
Kaeberlein
Matt
M
D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D031204:Caloric Restriction; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility; D005786:Gene Expression Regulation; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D008136:Longevity / Q000502:physiology; D008297:Male; D023421:Models, Animal; D010100:Oxygen / Q000502:physiology*; D010455:Peptides / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D044842:Cullin Proteins; C403074:Egl-9 protein, C elegans; C541178:HIF-1 protein, C elegans; D007328:Insulin; D010455:Peptides; D014157:Transcription Factors; C541177:VHL-1 protein, C elegans; C097188:polyglutamine; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen