COMMD1 promotes pVHL and O₂-independent proteolysis of HIF-1α via HSP90/70

Background: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-κB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for Commd1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL. Principal Findings: Here we characterized the mechanism by which COMMD1 regulates HIF-1a protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90b for binding to the NH₂-terminal DNA-binding and heterodimerization domain of HIF-1α to regulate HIF-1α stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1α degradation independent of ubiquitin and pVHL. Conclusion/Significance: These data reveal a novel role for COMMD1 in conjunction with HSP90β/HSP70 in the ubiquitin and O₂-independent regulation of HIF-1α.