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

Lookup NU author(s): Dr Catherine Park, Dr Iglika Ivanova, Dr Niall Kenneth

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. 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.


Publication metadata

Author(s): Park CV, Ivanova IG, Kenneth NS

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2017

Volume: 45

Issue: 16

Pages: 9336-9347

Print publication date: 19/09/2017

Online publication date: 28/06/2017

Acceptance date: 26/06/2017

Date deposited: 06/11/2017

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: https://doi.org/10.1093/nar/gkx549

DOI: 10.1093/nar/gkx549

PubMed id: 28666324


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