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

Abstract

Coordinating Response to Stress Sirtuin 1 (Sirt1) (a protein deacetylase implicated in aging), senses the metabolic state of the cell and modulates the activity of substrate proteins that in turn regulate cellular transcriptional responses. In response to hypoxia, cells activate the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α), which promotes adaptive responses. Dioum et al. (p. 1289 ; see the Perspective by Guarente ) discovered a link between these two important cellular stress response systems—HIF-2α is a substrate of Sirt1. Direct interaction between Sirt1 and HIF-2α results in deacetylation of HIF-2α and enhances its transcriptional activity. In mice lacking Sirt1, the ability of HIF-2α to promote synthesis of the growth factor erythropoietin is diminished. Thus, the regulation of HIF-2α helps to coordinate responses of cells to various stresses.