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Oxygen-dependent bond formation with FIH regulates the activity of the client protein OTUB1


Pickel, Christina; Günter, Julia; Ruiz-Serrano, Amalia; Spielmann, Patrick; Fabrizio, Jacqueline-Alba; Wolski, Witold; Peet, Daniel J; Wenger, Roland H; Scholz, Carsten C (2019). Oxygen-dependent bond formation with FIH regulates the activity of the client protein OTUB1. Redox Biology, 26:101265.

Abstract

Protein:protein interactions are the basis of molecular communication and are usually of transient non-covalent nature, while covalent interactions other than ubiquitination are rare. For cellular adaptations, the cellular oxygen and peroxide sensor factor inhibiting HIF (FIH) confers oxygen and oxidant stress sensitivity to the hypoxia inducible factor (HIF) by asparagine hydroxylation. We investigated whether FIH contributes to hypoxia adaptation also through other mechanisms and identified a hypoxia sensitive, likely covalent, bond formation by FIH with several client proteins, including the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1). Biochemical analyses were consistent with a co-translational amide bond formation between FIH and OTUB1, occurring within mammalian and bacterial cells but not between separately purified proteins. Bond formation is catalysed by FIH and highly dependent on oxygen availability in the cellular microenvironment. Within cells, a heterotrimeric complex is formed, consisting of two FIH and one covalently linked OTUB1. Complexation of OTUB1 by FIH regulates OTUB1 deubiquitinase activity. Our findings reveal an alternative mechanism for hypoxia adaptation with remarkably high oxygen sensitivity, mediated through covalent protein-protein interactions catalysed by an asparagine modifying dioxygenase.

Abstract

Protein:protein interactions are the basis of molecular communication and are usually of transient non-covalent nature, while covalent interactions other than ubiquitination are rare. For cellular adaptations, the cellular oxygen and peroxide sensor factor inhibiting HIF (FIH) confers oxygen and oxidant stress sensitivity to the hypoxia inducible factor (HIF) by asparagine hydroxylation. We investigated whether FIH contributes to hypoxia adaptation also through other mechanisms and identified a hypoxia sensitive, likely covalent, bond formation by FIH with several client proteins, including the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1). Biochemical analyses were consistent with a co-translational amide bond formation between FIH and OTUB1, occurring within mammalian and bacterial cells but not between separately purified proteins. Bond formation is catalysed by FIH and highly dependent on oxygen availability in the cellular microenvironment. Within cells, a heterotrimeric complex is formed, consisting of two FIH and one covalently linked OTUB1. Complexation of OTUB1 by FIH regulates OTUB1 deubiquitinase activity. Our findings reveal an alternative mechanism for hypoxia adaptation with remarkably high oxygen sensitivity, mediated through covalent protein-protein interactions catalysed by an asparagine modifying dioxygenase.

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Contributors:Functional Genomics Center Zurich, Dr. Peter Hunziker and Dr. Paolo Nanni for performing MS analyses, Daniel Prata for excellent technical support, Dr. Mu-Shui Dai (Oregon Health and Science University, Portland, Oregon, US) and Prof. Eric Metzen (University of Duisburg-Essen, Essen, Germany) for the kind gifts of plasmids
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 > Functional Genomics Center Zurich
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Organic Chemistry, Biochemistry
Language:English
Date:1 September 2019
Deposited On:12 Jul 2019 07:52
Last Modified:12 Jul 2019 08:02
Publisher:Elsevier
ISSN:2213-2317
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.redox.2019.101265
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_165679
  • : Project TitleHydroxylation-dependent functions of OTUB1 in oxygen physiology
  • : Funder
  • : Grant ID
  • : Project TitleJunior Grant of the NCCR Kidney.CH

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