FIH regulates cellular metabolism through hydroxylation of the deubiquitinase OTUB1.
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Authors
Scholz, Carsten C
Rodriguez, Javier
Pickel, Christina
Fabrizio, Jacqueline-alba
Nolan, Karen A
Spielmann, Patrick
Cavadas, Miguel AS
Crifo, Bianca
Halligan, Doug N
von, Kriegsheim Alex
Wenger, Roland H
Peet, Daniel J
Cummins, Eoin P
Taylor, Cormac T
Publication Date
2016-01-11Alternative Title
FIH regulates metabolism through OTUB1
Journal Title
PLoS Biology
ISSN
1544-9173
Publisher
PLoS
Volume
14
Number
e1002347
Language
English
Type
Article
Metadata
Show full item recordCitation
Scholz, C. C., Rodriguez, J., Pickel, C., Burr, S., Fabrizio, J., Nolan, K. A., Spielmann, P., et al. (2016). FIH regulates cellular metabolism through hydroxylation of the deubiquitinase OTUB1.. PLoS Biology, 14 (e1002347)https://doi.org/10.1371/journal.pbio.1002347
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 endogenous 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, mutant OTUB1 (lacking the hydroxylation site) impairs cellular metabolic processes when compared to wild type cells. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. We further propose that this provides new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.
Keywords
Hydroxylase, hypoxia, metabolism, ubiquitin, deubiquitinating enzyme, otubain, OTU domain
Sponsorship
Wellcome Trust (102770/Z/13/Z)
Wellcome Trust (100140/Z/12/Z)
Identifiers
External DOI: https://doi.org/10.1371/journal.pbio.1002347
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252577
Rights
Creative Commons Attribution 4.0 International License
Licence URL: http://creativecommons.org/licenses/by/4.0/