Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but not HIF-2α

Weibo Luo, Jun Zhong, Ryan Chang, Hongxia Hu, Akhilesh Pandey, Gregg L. Semenza

Research output: Contribution to journalArticle

Abstract

Hypoxia-inducible factors (HIFs) are transcription factors that mediate adaptive responses to reduced oxygen availability. HIF-α subunits are stabilized under conditions of acute hypoxia. However, prolonged hypoxia leads to decay of HIF-1α but not HIF-2α protein levels by unknown mechanisms. Here, we identify Hsp70 and CHIP (carboxyl terminus of Hsc70-interacting protein) as HIF-1α-interacting proteins. Hsp70, through recruiting the ubiquitin ligase CHIP, promotes the ubiquitination and proteasomal degradation of HIF-1α but not HIF-2α, thereby inhibiting HIF-1-dependent gene expression. Disruption of Hsp70-CHIP interaction blocks HIF-1α degradation mediated by Hsp70 and CHIP. Inhibition of Hsp70 or CHIP synthesis by RNA interference increases protein levels of HIF-1α but not HIF-2α and attenuates the decay of HIF-1α levels during prolonged hypoxia. Thus, Hsp70- and CHIP-dependent ubiquitination represents a molecular mechanism by which prolonged hypoxia selectively reduces the levels of HIF-1α but not HIF-2α protein.

Original languageEnglish (US)
Pages (from-to)3651-3663
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number6
DOIs
StatePublished - Feb 5 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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