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The conservation and functionality of the oxygen-sensing enzyme Factor Inhibiting HIF (FIH) in non-vertebrates

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dc.contributor.authorHampton-Smith, R.J.
dc.contributor.authorDavenport, B.A.
dc.contributor.authorNagarajan, Y.
dc.contributor.authorPeet, D.J.
dc.contributor.editorRocha, S.
dc.date.issued2019
dc.description.abstractThe asparaginyl hydroxylase, Factor Inhibiting HIF (FIH), is a cellular dioxygenase. Originally identified as oxygen sensor in the cellular response to hypoxia, where FIH acts as a repressor of the hypoxia inducible transcription factor alpha (HIF-α) proteins through asparaginyl hydroxylation, FIH also hydroxylates many proteins that contain ankyrin repeat domains (ARDs). Given FIH's promiscuity and the unclear functional effects of ARD hydroxylation, the biological relevance of HIF-α and ARD hydroxylation remains uncertain. Here, we have employed evolutionary and enzymatic analyses of FIH, and both HIF-α and ARD-containing substrates, in a broad range of metazoa to better understand their conservation and functional importance. Utilising Tribolium castaneum and Acropora millepora, we provide evidence that FIH from both species are able to hydroxylate HIF-α proteins, supporting conservation of this function beyond vertebrates. We further demonstrate that T. castaneum and A. millepora FIH homologs can also hydroxylate specific ARD proteins. Significantly, FIH is also conserved in several species with inefficiently-targeted or absent HIF, supporting the hypothesis of important HIF-independent functions for FIH. Overall, these data show that while oxygen-dependent HIF-α hydroxylation by FIH is highly conserved in many species, HIF-independent roles for FIH have evolved in others.
dc.description.statementofresponsibilityRachel J. Hampton-Smith, Briony A. Davenport, Yagnesh Nagarajan, Daniel J. Peet
dc.identifier.citationPLoS ONE, 2019; 14(4):0216134-1-0216134-29
dc.identifier.doi10.1371/journal.pone.0216134
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.orcidPeet, D.J. [0000-0002-6085-8936]
dc.identifier.urihttp://hdl.handle.net/2440/123883
dc.language.isoen
dc.publisherPublic Library of Science (PLoS)
dc.relation.granthttp://purl.org/au-research/grants/arc/DP150102860
dc.rights© 2019 Hampton-Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0216134
dc.subjectAnimals
dc.subjectHumans
dc.subjectTribolium
dc.subjectAnthozoa
dc.subjectMixed Function Oxygenases
dc.subjectEvolution, Molecular
dc.subjectSignal Transduction
dc.subjectCell Hypoxia
dc.subjectAmino Acid Sequence
dc.subjectAnkyrin Repeat
dc.subjectConserved Sequence
dc.subjectProtein Binding
dc.subjectSubstrate Specificity
dc.subjectHydroxylation
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit
dc.titleThe conservation and functionality of the oxygen-sensing enzyme Factor Inhibiting HIF (FIH) in non-vertebrates
dc.typeJournal article
pubs.publication-statusPublished

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