title: NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15.
abstract: Primary cilia are antenna-like sensory organelles protruding from the plasma membrane. Defects in ciliogenesis cause diverse genetic disorders. NDR2 was identified as the causal gene for a canine ciliopathy, early retinal degeneration, but its role in ciliogenesis remains unknown. Ciliary membranes are generated by transport and fusion of Golgi-derived vesicles to the pericentrosome, a process requiring Rab11-mediated recruitment of Rabin8, a GDP-GTP exchange factor (GEF) for Rab8, and subsequent Rab8 activation and Rabin8 binding to Sec15, a component of the exocyst that mediates vesicle tethering. This study shows that NDR2 phosphorylates Rabin8 at Ser-272 and defects in this phosphorylation impair preciliary membrane assembly and ciliogenesis, resulting in accumulation of Rabin8-/Rab11-containing vesicles at the pericentrosome. Rabin8 binds to and colocalizes with GTP-bound Rab11 and phosphatidylserine (PS) on pericentrosomal vesicles. The phospho-mimetic S272E mutation of Rabin8 decreases affinity for PS but increases affinity for Sec15. These results suggest that NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by triggering the switch in binding specificity of Rabin8 from PS to Sec15, thereby promoting local activation of Rab8 and ciliary membrane formation.
authors: Laboratory of Molecular Cell Biology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
authors: Shuhei
authors: S
authors: Chiba
authors: Yuta
authors: Y
authors: Amagai
authors: Yuta
authors: Y
authors: Homma
authors: Mitsunori
authors: M
authors: Fukuda
authors: Kensaku
authors: K
authors: Mizuno
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002923:Cilia / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004285:Dogs; D019204:GTP-Binding Proteins / Q000378:metabolism*; D000081410:Germinal Center Kinases; D006801:Humans; D010718:Phosphatidylserines / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology*; D061987:Sf9 Cells; D018411:Spodoptera; D013379:Substrate Specificity / Q000235:genetics
chemical_list: C489222:EXOC6B protein, human; D000081410:Germinal Center Kinases; D010718:Phosphatidylserines; D017346:Protein Serine-Threonine Kinases; C496014:STK38L protein, human; D019204:GTP-Binding Proteins