Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha.
Hypoxia-inducible factors (HIFs) are transcription factors that mediate adaptive responses to reduced oxygen availability. HIF-alpha subunits are stabilized under conditions of acute hypoxia. However, prolonged hypoxia leads to decay of HIF-1alpha but not HIF-2alpha protein levels by unknown mechanisms. Here, we identify Hsp70 and CHIP (carboxyl terminus of Hsc70-interacting protein) as HIF-1alpha-interacting proteins. Hsp70, through recruiting the ubiquitin ligase CHIP, promotes the ubiquitination and proteasomal degradation of HIF-1alpha but not HIF-2alpha, thereby inhibiting HIF-1-dependent gene expression. Disruption of Hsp70-CHIP interaction blocks HIF-1alpha degradation mediated by Hsp70 and CHIP. Inhibition of Hsp70 or CHIP synthesis by RNA interference increases protein levels of HIF-1alpha but not HIF-2alpha and attenuates the decay of HIF-1alpha levels during prolonged hypoxia. Thus, Hsp70- and CHIP-dependent ubiquitination represents a molecular mechanism by which prolonged hypoxia selectively reduces the levels of HIF-1alpha but not HIF-2alpha protein.
Luo
Weibo
W
From the Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Zhong
Jun
J
Departments of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Chang
Ryan
R
From the Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Hu
Hongxia
H
From the Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Pandey
Akhilesh
A
McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Semenza
Gregg L
GL
From the Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Departments of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. Electronic address: gsemenza@jhmi.edu.
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D018840:HSP70 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046988:Proteasome Endopeptidase Complex; D044767:Ubiquitin-Protein Ligases; D000099162:Endothelial PAS Domain-Containing Protein 1; C467728:STUB1 protein, human