Regulation of Hypoxia-Inducible Factor 2α Signaling by the Stress-Responsive Deacetylase Sirtuin 1

摘要

To survive in hostile environments, organisms activate stress-responsive transcriptional regulators that coordinately increase production of protective factors. Hypoxia changes cellular metabolism and thus activates redox-sensitive as well as oxygen-dependent signal transducers. We demonstrate that Sirtuin 1 (Sirt1), a redox-sensing deacetylase, selectively stimulates activity of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α) during hypoxia. The effect of Sirtl on HIF-2α required direct interaction of the proteins and intact deacetylase activity of Sirtl. Select lysine residues in HIF-2α that are acetylated during hypoxia confer repression of Sirtl augmentation by small-molecule inhibitors. In cultured cells and mice, decreasing or increasing Sirtl activity or levels affected expression of the HIF-2α target gene erythropoietin accordingly. Thus, Sirtl promotes HIF-2 signaling during hypoxia and likely other environmental stresses.