PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function.
PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function.
复制标题
DOI：
10.1016/j.devcel.2014.01.022
复制
发表时间：
2014-03-31
影响因子：
11.8
通讯作者：
Hirsch, Emilio
中科院分区：
文献类型：
--
作者：
Franco, Irene;Gulluni, Federico;Campa, Carlo C.;Costa, Carlotta;Margaria, Jean Piero;Ciraolo, Elisa;Martini, Miriam;Monteyne, Daniel;De Luca, Elisa;Germena, Giulia;Posor, York;Maffucci, Tania;Marengo, Stefano;Haucke, Volker;Falasca, Marco;Perez-Morga, David;Boletta, Alessandra;Merlo, Giorgio R.;Hirsch, Emilio
多种磷脂酰肌醇（PtdIns）3-激酶（PI 3 Ks）可以产生PtdIns 3 P来控制内吞转运，但酶的特化是否发生在确定的亚细胞位置尚不清楚。在这里，我们报告说，PI 3 K-C2 α是丰富的，在中央循环内吞区室（PRE）的基础上的初级纤毛，在那里它调节生产的特定池PtdIns 3 P。PI 3 K-C2 α衍生的PtdIns 3 P的缺失导致PRE标记物如TfR和Rab 11的错误定位，减少Rab 11的活化，并阻断Rab 8在初级纤毛中的积累。这些变化反过来导致初级纤毛伸长、Smo纤毛移位和Sonic Hedgehog（Shh）信号传导的缺陷，并最终损害胚胎发育。在缺乏PI 3 K-C2 α的细胞中选择性重建PtdIns 3 P水平拯救Rab 11活化、初级纤毛长度和Shh途径诱导。因此，PI 3 K-C2 α调节Rab 11和Shh通路激活所需的PRE处PtdIns 3 P池的形成。PI 3 K-C2 α在PRE特异性产生PtdIns 3 P PI 3 K-C2 α依赖性PtdIns 3 P调节Rab 11的定位和激活PI 3 K-C2 α控制初级纤毛基底的Rab 11/Rab 8轴PI 3 K-C2 α是Smo纤毛靶向和Shh信号传导所需的。Franco等人报道PI 3 K-C2 α在初级纤毛基部周围的中心粒周围再循环内吞区室（PRE）中富集，并调节Rab 11定位/激活、Smo纤毛靶向和Shh信号传导所需的PtdIns 3 P依赖性膜运输。
Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3P to control endocytic trafficking, but whether enzyme specialization occurs in defined subcellular locations is unclear. Here, we report that PI3K-C2α is enriched in the pericentriolar recycling endocytic compartment (PRE) at the base of the primary cilium, where it regulates production of a specific pool of PtdIns3P. Loss of PI3K-C2α-derived PtdIns3P leads to mislocalization of PRE markers such as TfR and Rab11, reduces Rab11 activation, and blocks accumulation of Rab8 at the primary cilium. These changes in turn cause defects in primary cilium elongation, Smo ciliary translocation, and Sonic Hedgehog (Shh) signaling and ultimately impair embryonic development. Selective reconstitution of PtdIns3P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3P pool at the PRE required for Rab11 and Shh pathway activation. PI3K-C2α specifically produces PtdIns3P at the PRE PI3K-C2α-dependent PtdIns3P modulates localization and activation of Rab11 PI3K-C2α controls the Rab11/Rab8 axis at the primary cilium base PI3K-C2α is required for Smo ciliary targeting and Shh signaling Multiple PI3Ks produce PtdIns3P, but whether enzyme specialization occurs in defined subcellular locations is unclear. Franco et al. report that PI3K-C2α is enriched in the pericentriolar recycling endocytic compartment (PRE) around the primary cilium base and regulates PtdIns3P-dependent membrane traffic required for Rab11 localization/activation, Smo ciliary targeting, and Shh signaling.
登录
查看更多内容
影响因子：
--
作者：
Hsiao YC;Tuz K;Ferland RJ
通讯作者：
Ferland RJ
DOI：
10.1083/jcb.200907126
发表时间：
2009-11-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Milenkovic L;Scott MP;Rohatgi R
通讯作者：
Rohatgi R
影响因子：
5.6
作者：
Eathiraj, Sudharshan;Mishra, Ashwini;Lambright, David G.
通讯作者：
Lambright, David G.
影响因子：
50.3
作者：
Gewinner C;Wang ZC;Richardson A;Teruya-Feldstein J;Etemadmoghadam D;Bowtell D;Barretina J;Lin WM;Rameh L;Salmena L;Pandolfi PP;Cantley LC
通讯作者：
Cantley LC
影响因子：
64.8
作者：
通讯作者：
--