Ciliopathy Protein Hyls1 Coordinates The Biogenesis And Signaling Of Primary Cilia By Activating The Ciliary Lipid Kinase Pipki Gamma

Mutation of ciliopathy protein HYLS1 causes the perinatal lethal hydrolethalus syndrome (HLS), yet the underlying molecular etiology and pathogenesis remain elusive. Here, we reveal unexpected mechanistic insights into the role of mammalian HYLS1 in regulating primary cilia. HYLS1 is recruited to the ciliary base via a direct interaction with the type I gamma phosphatidylinositol 4-phosphate [PI(4)P] 5-kinase (PIPKI gamma). HYLS1 activates PIPKI gamma by interrupting the autoinhibitory dimerization of PIPKI gamma, which thereby expedites depletion of centrosomal PI(4)P to allow axoneme nucleation. HYLS1 deficiency interrupts the assembly of ciliary NPHP module and agonist-induced ciliary exit of beta-arrestin, which, in turn, disturbs the removal of ciliary Gpr161 and activation of hedgehog (Hh) signaling. Consistent with this model of pathogenesis, the HLS mutant HYLS1(D211G) supports ciliogenesis but not activation of Hh signaling. These results implicate mammalian HYLS1 as a multitasking protein that facilitates ciliogenesis and ciliary signaling by coordinating with the ciliary lipid kinase PIPKI gamma.