title: Oxygen-dependent hydroxylation by FIH regulates the TRPV3 ion channel.
abstract: Factor inhibiting HIF (FIH, also known as HIF1AN) is an oxygen-dependent asparaginyl hydroxylase that regulates the hypoxia-inducible factors (HIFs). Several proteins containing ankyrin repeat domains (ARDs) have been characterised as substrates of FIH, although there is little evidence for a functional consequence of hydroxylation on these substrates. This study demonstrates that the transient receptor potential vanilloid 3 (TRPV3) channel is hydroxylated by FIH on asparagine 242 within the cytoplasmic ARD. Hypoxia, FIH inhibitors and mutation of asparagine 242 all potentiated TRPV3-mediated current, without altering TRPV3 protein levels, indicating that oxygen-dependent hydroxylation inhibits TRPV3 activity. This novel mechanism of channel regulation by oxygen-dependent asparaginyl hydroxylation is likely to extend to other ion channels.
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, SA, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Karttunen
authors.affiliation: School of Medicine, University of Adelaide, Adelaide 5005, South Australia, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Duffield
authors.affiliation: School of Medicine, University of Adelaide, Adelaide 5005, South Australia, Australia.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Scrimgeour
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, SA, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Squires
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, SA, Australia.
authors.forename: Wai Li
authors.initials: WL
authors.lastname: Lim
authors.affiliation: Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dallas
authors.affiliation: Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Scragg
authors.affiliation: Protein Discovery Centre, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
authors.forename: Johana
authors.initials: J
authors.lastname: Chicher
authors.affiliation: Protein Discovery Centre, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
authors.forename: Keyur A
authors.initials: KA
authors.lastname: Dave
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, SA, Australia.
authors.forename: Murray L
authors.initials: ML
authors.lastname: Whitelaw
authors.affiliation: Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.affiliation: Protein Discovery Centre, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gorman
authors.affiliation: Department of Renal Medicine, School of Medicine, Flinders University Flinders Medical Centre, Bedford Park, SA 5042, Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gleadle
authors.affiliation: School of Medicine, University of Adelaide, Adelaide 5005, South Australia, Australia.
authors.forename: Grigori Y
authors.initials: GY
authors.lastname: Rychkov
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, SA, Australia Centre for Molecular Pathology, University of Adelaide, Adelaide, SA 5005, Australia daniel.peet@adelaide.edu.au.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Peet
mesh_terms: D000595:Amino Acid Sequence; D017089:Ankyrin Repeat / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D006900:Hydroxylation / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; D050916:TRPV Cation Channels; C459445:TRPV3 protein, human; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D010100:Oxygen
keywords: FIH; Hydroxylation; Hypoxia; TRPV3