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

131 Citations (Scopus)

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

Fingerprint

HSC70 Heat-Shock Proteins
Hypoxia-Inducible Factor 1
Ubiquitination
Degradation
Proteins
endothelial PAS domain-containing protein 1
Ligases
Ubiquitin
RNA Interference
Hypoxia
Transcription Factors
Gene expression
Oxygen
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but not HIF-2α. / Luo, Weibo; Zhong, Jun; Chang, Ryan; Hu, Hongxia; Pandey, Akhilesh; Semenza, Gregg L.

In: Journal of Biological Chemistry, Vol. 285, No. 6, 05.02.2010, p. 3651-3663.

Research output: Contribution to journalArticle

Luo, Weibo ; Zhong, Jun ; Chang, Ryan ; Hu, Hongxia ; Pandey, Akhilesh ; Semenza, Gregg L. / Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but not HIF-2α. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 6. pp. 3651-3663.
@article{f30f3bfcf0c64e79b89ecee83acf3e5e,
title = "Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but not HIF-2α",
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.",
author = "Weibo Luo and Jun Zhong and Ryan Chang and Hongxia Hu and Akhilesh Pandey and Semenza, {Gregg L.}",
year = "2010",
month = "2",
day = "5",
doi = "10.1074/jbc.M109.068577",
language = "English (US)",
volume = "285",
pages = "3651--3663",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but not HIF-2α

AU - Luo, Weibo

AU - Zhong, Jun

AU - Chang, Ryan

AU - Hu, Hongxia

AU - Pandey, Akhilesh

AU - Semenza, Gregg L.

PY - 2010/2/5

Y1 - 2010/2/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77950473770&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950473770&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.068577

DO - 10.1074/jbc.M109.068577

M3 - Article

C2 - 19940151

AN - SCOPUS:77950473770

VL - 285

SP - 3651

EP - 3663

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -