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Modulation of ciliary phosphoinositide content regulates trafficking and Sonic Hedgehog signaling output.

par Chavez Garcia, Edison ;Ena, Sabrina ;Van Sande, Jacqueline ;de Kerchove d'Exaerde, Alban ;Schurmans, Stéphane ;Schiffmann, Serge N.
Référence Developmental cell, 34, page (338-350)
Publication Publié, 2015-07-16

Article révisé par les pairs

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Résumé :

Ciliary transport is required for ciliogenesis, signal transduction, and trafficking of receptors to the primary cilium. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) have been associated with ciliary dysfunction; however, its role in regulating ciliary phosphoinositides is unknown. Here we report that in neural stem cells, phosphatidylinositol 4-phosphate (PI4P) is found in high levels in cilia whereas phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) is not detectable. Upon INPP5E inactivation, PI(4,5)P2 accumulates at the ciliary tip whereas PI4P is depleted. This is accompanied by recruitment of the PI(4,5)P2-interacting protein TULP3 to the ciliary membrane, along with Gpr161. This results in an increased production of cAMP and a repression of the Shh transcription gene Gli1. Our results reveal the link between ciliary regulation of phosphoinositides by INPP5E and Shh regulation via ciliary trafficking of TULP3/Gpr161 and also provide mechanistic insight into ciliary alterations found in Joubert and MORM syndromes resulting from INPP5E mutations. Chávez et al. identify the main phosphoinositide species in neural stem cell primary cilia and show that the PIP phosphatase INPP5E regulates their levels. Loss of INPP5E changes the dominant cilium phosphoinositide species and affects recruitment of the PIP-interacting protein TULP3 and its cargo Gpr161, with effects on Shh signaling.