Molecular mechanisms of INPP5E-dependent cilia disassembly

Resumen del póster presentado al 42nd Congress of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), celebrado en Madrid del 16 al 19 de julio de 2019.Primary cilia are microtubule-based plasma membrane protrusions that function as cellular antennae whose dysfunction causes ciliopathies and cancer. Since both primary cilia and mitotic spindles engage centrosomes, ciliated cells must disassemble their cilia in order to divide. Cilia disassembly is stimulated by growth factors (GFs) and involves two parallel processes: (i) HDAC6-mediated microtubule deacetylation and resorption (axoneme resorption), and (ii) PI(4,5)P2 and F-actin-dependent membrane vesicle release from the ciliary tip (cilia decapitation). GFs act partly by downregulating INPP5E, a ciliary PI(4,5)P2 5-phosphatase. Without INPP5E, axonemes resorb faster in response to GFs, and cilia decapitation becomes GF-independent. However, how GFs repress INPP5E, and how the latter's repression leads to cilia disassembly remains unclear. Here, we show that active GF receptors promote tyrosine phosphorylation of INPP5E, which also binds GRB2, a key adapter in GF signaling. Moreover, a phosphotyrosine-mimetic INPP5E mutant fails to localize to cilia, consistent with previous data showing GFs reduce INPP5E ciliary targeting. We also find INPP5E binds HDAC6 and promotes axoneme acetylation, possibly explaining why INPP5E mutant axonemes resorb faster. Furthermore, INPP5E interacts with F-actin regulators SNX9 and Endophilin A2, through which it may promote cilia decapitation.Peer reviewe