XIAP upregulates expression of HIF target genes by targeting HIF1α for Lys63-linked polyubiquitination

The cellular response to hypoxia is characterised by a switch in the transcriptional program, mediated predominantly by the hypoxia inducible factor family of transcription factors (HIF). Regulation of HIF1 is primarily controlled by post-translational modification of the HIF1 alpha subunit, which can alter its stability and/or activity. This study identifies an unanticipated role for the X-linked inhibitor of apoptosis (XIAP) protein as a regulator of Lys(63)-linked polyubiquitination of HIF1 alpha. Lys(63)-linked ubiquitination of HIF1 alpha by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13. We find that XIAP and Ubc13 dependent Lys(63)-linked polyubiquitination promotes HIF1 alpha nuclear retention leading to an increase in the expression of HIF1 responsive genes. Inhibition of the Lys(63)-linked polyubiquitination pathway leads to reduced levels of nuclear HIF1 alpha, promoter occupancy, HIF-dependent gene expression and cell viability. Our data reveals an additional and significant level of control of the HIF1 by XIAP, with important implications in understanding the role of HIF1 and XIAP in human disease.