MYLIP attenuates hypoxia tolerance by inducing K27-linked polyubiquitination and subsequent proteasomal degradation of HIF-α.

Hypoxia tolerance is mainly controlled by the hypoxia signaling pathway and HIF-1α/2α serve as master regulators in this pathway. Here we identify MYLIP, an E3 ubiquitin ligase thought to specifically target lipoprotein receptors, as a downstream target of HIF-2α and a negative regulator of both HIF-1α and HIF-2α. MYLIP interacts with HIF-1α/2α and catalyzes K27-linked polyubiquitination at lysine 118/442 (HIF-1α) or lysine 117 (HIF-2α). This modification induces proteasomal degradation of HIF-1α, resulting in inhibition of hypoxia signaling. Furthermore, Mylip-deficient bluntsnout bream, zebrafish and mice are more tolerant to hypoxia. These findings reveal a role for MYLIP in regulating hypoxia signaling and identify a target for the development of fish strains with high hypoxia tolerance for the benefit of the aquaculture industry.