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.
Highlights
Defective primary cilia are causative to a wide spectrum of human genetic disorders, termed ciliopathies
Our previous work describing the function of PIPKIg at the centrosome32 suggests that PIPKIg might participate in the context of cilia when the M-centriole transforms into the basal body
Considering PIPKIg and inositol polyphosphate-5-phosphatase E (INPP5E) are counteracting enzymes, these results suggest that the level of corresponding PIs (PtdIns[4]P and/or PtdIns[4,5]P2) around the M-centriole/basal body ought to be changed before and after ciliogenesis
Summary
Defective primary cilia are causative to a wide spectrum of human genetic disorders, termed ciliopathies. Two groups independently reported that INPP5E localizes in primary cilia and maintains a PtdIns[4]P-high, PtdIns[4,5]P2-low environment, which ensures the processing of hedgehog signalling by inhibiting the ciliary entry of TULP3 and Gpr161 (refs 30,31) These studies clearly support the importance of PIs in ciliary signalling; whether and how these phospholipids participate in ciliogenesis is unclear. Further investigation demonstrates a centrosomal pool of PtdIns[4]P, a product of INPP5E and the substrate of PIPKIg, prevents the recruitment of TTBK2 to the M-centriole by binding to CEP164 and TTBK2, and inhibiting the TTBK2-CEP164 interaction Overall, these discoveries reveal a novel mechanism that PIPKIg and INPP5E coordinate the initiation of ciliogenesis by spatiotemporally regulating a centrosomal PtdIns[4]P pool to control the TTBK2 recruitment and CP110 removal
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