On Monday evening, Octobe 9, Maxense Nachury, PhD, Stanford & UCSF, spoke on “Molecular Mechanisms and Functional Significance of EV Secretion by Primary Cilia.” He noted that the primary cilium, present on almost all cells, is a microtubule-based projection with its own complement of protein, lipids, and second messengers. The primary cilia have long been recognized for their roles in phototransduction and olfactory signaling. In recent years, cilia have been found to organize the developmental signaling pathway Sonic Hedgehog and various neuronal signaling pathways mediated by G-protein-coupled receptors (GPCRs). Dr. Nachury said that a hallmark of ciliary signaling pathways is the dynamic delivery and removal of ciliary proteins. Activated ciliary GPCRs are retrieved back into the cell through beta-arrestin2- and BBSome-mediated transport. (The BBSome is an octameric protein complex that is a component of the basal body and is involved in trafficking cargos to the primary cilium). Surprisingly, Dr. Nachury said, when retrieval is compromised, activated GPCRs become selectively concentrated into membranous buds at the tip of cilia, and actin-mediated scission releases extracellular vesicles (EVs) packaged with activated GPCRs. The microtubule-actin crosslinker Drebrin and Myosin VII localize to the site of ectosome release at the ciliary tip under ectosome-producing conditions and are required for the scission of EVs from the tip of cilia. Signal-dependent ectocytosis also applies to physiological context, where it removes, from cilia, specific GPCRs such as anorexigenic receptor NPY2R that lack retrieval determinants. Functionally, ciliary ectocytosis is required for the appropriate reulation of Hedgehog signaling in retrieval mutants. Dr. Nachury said these results show that signal-dependent ectocytosis mirrors receptor-mediated endocytosis as an evolutionarily conserved process that removes activated receptors from the cell surface to alter signaling processes.
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