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.
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U2 - 10.1074/jbc.M109.068577
DO - 10.1074/jbc.M109.068577
M3 - Article
C2 - 19940151
AN - SCOPUS:77950473770
SN - 0021-9258
VL - 285
SP - 3651
EP - 3663
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -