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FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1


Abstract

The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.

Abstract

The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.

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Contributors:Dr. Eric Metzen, University of Duisburg-Essen, Essen, Germany, Dr. Mu-Shui Dai, Oregon Health and Science University, Portland, Oregon, US, Dr. Wade Harper, Harvard Medical School, Boston, Massachusettes, US
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:11 January 2016
Deposited On:21 Jan 2016 11:59
Last Modified:18 Apr 2018 11:47
Publisher:Public Library of Science (PLoS)
ISSN:1544-9173
Funders:Science Foundation Ireland (SFI), Systems Biology Ireland (SBI), Starting Investigator Research Grant from SFI (SFI-SIRG), Wellcome Trust Senior Clinical Research Fellowship, A grant from the Australian Research Council, Forschungskredit of the University of Zurich, Funding from the EU 7th Framework Programme, NCCR Kidney.CH, Swiss National Science Foundation
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.pbio.1002347
PubMed ID:26752685
Project Information:
  • : FunderFP7
  • : Grant ID608847
  • : Project TitleIKPP2 - International Fellowship Program on Integrative Kidney Physiology and Pathophysiology
  • : Funder
  • : Grant ID
  • : Project TitleScience Foundation Ireland (SFI)
  • : Funder
  • : Grant ID
  • : Project TitleSystems Biology Ireland (SBI)
  • : Funder
  • : Grant ID
  • : Project TitleStarting Investigator Research Grant from SFI (SFI-SIRG)
  • : Funder
  • : Grant ID
  • : Project TitleWellcome Trust Senior Clinical Research Fellowship
  • : Funder
  • : Grant ID
  • : Project TitleA grant from the Australian Research Council
  • : Funder
  • : Grant ID
  • : Project TitleForschungskredit of the University of Zurich
  • : Funder
  • : Grant ID
  • : Project TitleFunding from the EU 7th Framework Programme
  • : Funder
  • : Grant ID
  • : Project TitleNCCR Kidney.CH
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation

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