title: KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability.
abstract: Cilia assembly and disassembly are coupled to actin dynamics, ensuring a coherent cellular response during environmental change. How these processes are integrated remains undefined. The histone lysine demethylase KDM3A plays important roles in organismal homeostasis. Loss-of-function mouse models ofKdm3aphenocopy features associated with human ciliopathies, whereas human somatic mutations correlate with poor cancer prognosis. We demonstrate that absence of KDM3A facilitates ciliogenesis, but these resulting cilia have an abnormally wide range of axonemal lengths, delaying disassembly and accumulating intraflagellar transport (IFT) proteins. KDM3A plays a dual role by regulating actin gene expression and binding to the actin cytoskeleton, creating a responsive "actin gate" that involves ARP2/3 activity and IFT. Promoting actin filament formation rescuesKDM3Amutant ciliary defects. Conversely, the simultaneous depolymerization of actin networks and IFT overexpression mimics the abnormal ciliary traits ofKDM3Amutants. KDM3A is thus a negative regulator of ciliogenesis required for the controlled recruitment of IFT proteins into cilia through the modulation of actin dynamics.
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK patricia.yeyati@igmm.ed.ac.uk pleasantine.mill@igmm.ed.ac.uk.
authors.forename: Patricia L
authors.identifier: 0000-0001-5094-5182
authors.initials: PL
authors.lastname: Yeyati
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, OX1 3TA Oxford, England, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiller
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Girish
authors.identifier: 0000-0002-5551-7555
authors.initials: G
authors.lastname: Mali
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Ioannis
authors.identifier: 0000-0001-5054-5357
authors.initials: I
authors.lastname: Kasioulis
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, OX1 3TA Oxford, England, UK.
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Ian R
authors.identifier: 0000-0001-8838-1271
authors.initials: IR
authors.lastname: Adams
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Christopher
authors.identifier: 0000-0002-3013-4005
authors.initials: C
authors.lastname: Playfoot
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Gilbert
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Veronica
authors.identifier: 0000-0003-0359-0141
authors.initials: V
authors.lastname: van Heyningen
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Jimi
authors.initials: J
authors.lastname: Wills
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Andrew
authors.identifier: 0000-0002-8065-4623
authors.initials: A
authors.lastname: Finch
authors.affiliation: Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Juro
authors.identifier: 0000-0003-4043-1035
authors.initials: J
authors.lastname: Sakai
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, OX1 3TA Oxford, England, UK.
authors.forename: Christopher J
authors.identifier: 0000-0002-0290-6565
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK.
authors.forename: Ian J
authors.identifier: 0000-0001-6526-0688
authors.initials: IJ
authors.lastname: Jackson
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU Scotland, UK patricia.yeyati@igmm.ed.ac.uk pleasantine.mill@igmm.ed.ac.uk.
authors.forename: Pleasantine
authors.initials: P
authors.lastname: Mill
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D002460:Cell Line; D002923:Cilia / Q000378:metabolism / Q000502:physiology*; D005407:Flagella / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis / Q000502:physiology; D009154:Mutation / Q000502:physiology; D010641:Phenotype
chemical_list: D000199:Actins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases