TY - JOUR
T1 - Phosphatidylinositol phosphate kinase PIPKIγ and phosphatase INPP5E coordinate initiation of ciliogenesis
AU - Xu, Qingwen
AU - Zhang, Yuxia
AU - Wei, Qing
AU - Huang, Yan
AU - Hu, Jinghua
AU - Ling, Kun
N1 - Funding Information:
We thank Dr Marcelo Chávez (Université Libre de Bruxelles, Belgium), Drs Jeremy Reiter and Francesc Garcia-Gonzalo (UCSF, San Francisco, CA) for sharing their immunofluorescence staining methods. We thank Dr Kathryn Anderson (Sloan-Kettering Institute, New York, NY) for sharing the GFP-TTBK2 plasmid and Dr Seongjin Seo (University of Iowa, Iowa City, IA) for providing the Flag-INPP5E plasmid. We thank Trace Christensen and Scott Gamb (Electron Microscopy Core Facility, Mayo Clinic) for technical assistance with electron microscope studies. K.L., Q.X. and Y.H. are supported by research grants from NCI (1R01-CA149039) and NIDDK (DK90728). J.H., Y.Z. and Q.W. are supported by NIH/NIDDK (1R01-DK090038).
PY - 2016/2/26
Y1 - 2016/2/26
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms10777
DO - 10.1038/ncomms10777
M3 - Article
C2 - 26916822
AN - SCOPUS:84959277845
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 10777
ER -