XIAP upregulates expression of HIF target genes by targeting HIF1 alpha for Lys(63)-linked polyubiquitination



Park, Catherine V, Ivanova, Iglika G and Kenneth, Niall S ORCID: 0000-0001-8528-1021
(2017) XIAP upregulates expression of HIF target genes by targeting HIF1 alpha for Lys(63)-linked polyubiquitination. Nucleic Acids Research, 45 (16). 9336 - 9347.

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Abstract

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 HIF1α 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 Lys63-linked polyubiquitination of HIF1α. Lys63-linked ubiquitination of HIF1α by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13. We find that XIAP and Ubc13 dependent Lys63-linked polyubiquitination promotes HIF1α nuclear retention leading to an increase in the expression of HIF1 responsive genes. Inhibition of the Lys63-linked polyubiquitination pathway leads to reduced levels of nuclear HIF1α, 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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 21 Jul 2020 08:08
Last Modified: 18 Aug 2022 14:11
DOI: 10.1093/nar/gkx549
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3094662