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论文摘要：	Hypoxia tolerance is mainly controlled by the hypoxia signaling pathway and HIF-1 alpha/2 alpha 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-2 alpha and a negative regulator of both HIF-1 alpha and HIF-2 alpha. MYLIP interacts with HIF-1 alpha/2 alpha and catalyzes K27-linked polyubiquitination at lysine 118/442 (HIF-1 alpha) or lysine 117 (HIF-2 alpha). This modification induces proteasomal degradation of HIF-1 alpha, 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.

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