Xu Qingwen, Zhang Yuxia, Wei Qing, Huang Yan, Hu Jinghua, Ling Kun
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
Nat Commun. 2016 Feb 26;7:10777. doi: 10.1038/ncomms10777.
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.
原发性纤毛缺陷可导致多种人类遗传疾病，即纤毛病。尽管对纤毛发生的调控进行了深入研究，但其起始机制仍不清楚。在这里，我们表明Iγ型磷脂酰肌醇4-磷酸（PtdIns(4)P）5-激酶（PIPKIγ）和一种与乔布综合征相关的蛋白——肌醇多磷酸-5-磷酸酶E（INPP5E），定位于中心体，并协同启动纤毛发生。在调节微管蛋白激酶2（TTBK2）募集到基体的过程中，PIPKIγ与INPP5E相互拮抗，这促进了微管加帽蛋白CP110的去除以及随后轴丝的伸长。有趣的是，INPP5E及其产物——PtdIns(4)P——在未形成纤毛的细胞的中心体/基体处积累，而在已形成纤毛的细胞中则不会。PtdIns(4)P与TTBK2和远端附属蛋白CEP164结合会损害TTBK2与CEP164的相互作用，并抑制TTBK2的募集。我们的结果表明，由PIPKIγ和INPP5E在中心体/纤毛基部协调的PtdIns(4)P稳态，通过调节CEP164依赖的TTBK2募集对纤毛发生至关重要。
