Distinct aerobic and hypoxic mechanisms of HIF-α regulation by CSN5

Mammalian oxygen homeostasis is dependent on the HIF family of transcription factors. The CSN subunit, CSN5, binds both the CODD of HIF-1alpha and the pVHL tumor suppressor. High CSN5 expression generates a pVHL-independent form of CSN5 that stabilizes HIF-1alpha aerobically by inhibiting HIF-1alpha prolyl-564 hydroxylation. Aerobic CSN5 association with HIF-1alpha occurs independently of the CSN holocomplex, leading to HIF-1alpha stabilization independent of Cullin 2 deneddylation. CSN5 weakly associates with HIF-1alpha under hypoxia, but is required for optimal hypoxia-mediated HIF-1alpha stabilization. These results indicate that CSN5 regulates aerobic as well as hypoxic HIF-1alpha stability by different mechanisms during oncogenesis.