title: Phosphatidylinositol phosphate kinase PIPKIγ and phosphatase INPP5E coordinate initiation of ciliogenesis.
abstract: Defective primary cilia are causative to a wide spectrum of human genetic disorders, termed ciliopathies. Although the regulation of ciliogenesis is intensively studied, how it is initiated remains unclear. Here we show that type Iγ phosphatidylinositol 4-phosphate (PtdIns(4)P) 5-kinase (PIPKIγ) and inositol polyphosphate-5-phosphatase E (INPP5E), a Joubert syndrome protein, localize to the centrosome and coordinate the initiation of ciliogenesis. PIPKIγ counteracts INPP5E in regulating tau-tubulin kinase-2 (TTBK2) recruitment to the basal body, which promotes the removal of microtubule capping protein CP110 and the subsequent axoneme elongation. Interestingly, INPP5E and its product--PtdIns(4)P--accumulate at the centrosome/basal body in non-ciliated, but not ciliated, cells. PtdIns(4)P binding to TTBK2 and the distal appendage protein CEP164 compromises the TTBK2-CEP164 interaction and inhibits the recruitment of TTBK2. Our results reveal that PtdIns(4)P homoeostasis, coordinated by PIPKIγ and INPP5E at the centrosome/ciliary base, is vital for ciliogenesis by regulating the CEP164-dependent recruitment of TTBK2.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.|Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Ling
mesh_terms: D000818:Animals; D018385:Centrosome / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009024:Morphogenesis / Q000235:genetics*; D041681:NIH 3T3 Cells; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D000099182:Phosphoinositide 5-Phosphatases; C095903:tau-tubulin kinase; C020077:1-phosphatidylinositol-4-phosphate 5-kinase