title: HEATR2 plays a conserved role in assembly of the ciliary motile apparatus.
abstract: Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme.
authors.affiliation: School of Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Diggle
authors.affiliation: Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Girish
authors.initials: G
authors.lastname: Mali
authors.affiliation: Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Petra
authors.initials: P
authors.lastname: zur Lage
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, Université de Genève, Geneva, Switzerland.
authors.forename: Aouatef
authors.initials: A
authors.lastname: Ait-Lounis
authors.affiliation: Molecular Medicine Unit and Birth Defect Research Center, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.affiliation: Paediatric Respiratory Department, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Amaya
authors.initials: A
authors.lastname: Garcia Munoz
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Mihail R
authors.initials: MR
authors.lastname: Halachev
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gautier
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Yeyati
authors.affiliation: School of Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.affiliation: School of Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.affiliation: School of Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Bruce
authors.initials: B
authors.lastname: Hayward
authors.affiliation: School of Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.affiliation: Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jilly E
authors.initials: JE
authors.lastname: Hope
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
authors.affiliation: Molecular Medicine Unit and Birth Defect Research Center, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.affiliation: Centre de Génétique et de Physiologie Moléculaire et Cellulaire, UMR 5534 CNRS, Université Claude Bernard Lyon 1, Villeurbanne, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Durand
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, Université de Genève, Geneva, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.affiliation: School of Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jarman
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Pleasantine
authors.initials: P
authors.lastname: Mill
mesh_terms: D000818:Animals; D056444:Axonemal Dyneins; D054468:Axoneme / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002675:Child, Preschool; D002923:Cilia / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002925:Ciliary Motility Disorders / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C578870:DNAAF5 protein, human; D011506:Proteins; D056444:Axonemal Dyneins; D004398:Dyneins