NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15
NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15
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DOI：
10.1038/emboj.2013.32
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发表时间：
2013-03-20
期刊：
影响因子：
11.4
通讯作者：
Mizuno, Kensaku
中科院分区：
文献类型：
--
作者：
Chiba, Shuhei;Amagai, Yuta;Mizuno, Kensaku
初级纤毛是从质膜伸出的触角状感觉细胞器。纤毛发生缺陷导致多种遗传疾病。NDR 2被鉴定为犬睫状体病（早期视网膜变性）的致病基因，但其在纤毛发生中的作用仍不清楚。睫状体膜是由高尔基体衍生的囊泡运输和融合到中心体周围产生的，这一过程需要Rab 11介导的Rabin 8的募集，Rab 8的GDP-GTP交换因子（GEF），以及随后Rab 8的激活和Rabin 8与Sec 15的结合，Sec 15是介导囊泡束缚的外囊组分。这项研究表明，NDR 2在Ser-272磷酸化Rabin 8，这种磷酸化的缺陷会损害睫状前膜组装和纤毛发生，导致含有Rabin 8/Rab 11的囊泡在核周体处积累。Rabin 8与GTP结合的Rab 11和磷脂酰丝氨酸（PS）结合并共定位于粒周囊泡上。Rabin 8的磷酸模拟S272 E突变降低了对PS的亲和力，但增加了对Sec 15的亲和力。这些结果表明，NDR 2介导的Rabin 8磷酸化通过触发Rabin 8从PS到Sec 15的结合特异性的转换，从而促进Rab 8的局部激活和睫状膜形成，对纤毛发生至关重要。The EMBO Journal（2013）32，874-885. doi：10.1038/daj.2013.32; 2013年2月22日在线发布
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 pre-ciliary 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. The EMBO Journal (2013) 32, 874-885. doi:10.1038/emboj.2013.32; Published online 22 February 2013