CAS Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.
Cell Res. 2012 Feb;22(2):333-45. doi: 10.1038/cr.2011.134. Epub 2011 Aug 16.
Sorting nexins (SNXs) are phosphoinositide-binding proteins implicated in the sorting of various membrane proteins in vitro, but the in vivo functions of them remain largely unknown. We reported previously that SNX10 is a unique member of the SNX family genes in that it has vacuolation activity in cells. We investigate the biological function of SNX10 by loss-of-function assay in this study and demonstrate that SNX10 is required for the formation of primary cilia in cultured cells. In zebrafish, SNX10 is involved in ciliogenesis in the Kupffer's vesicle and essential for left-right patterning of visceral organs. Mechanistically, SNX10 interacts with V-ATPase complex and targets it to the centrosome where ciliogenesis is initiated. Like SNX10, V-ATPase regulates ciliogenesis in vitro and in vivo and does so synergistically with SNX10. We further discover that SNX10 and V-ATPase regulate the ciliary trafficking of Rab8a, which is a critical regulator of ciliary membrane extension. These results identify an SNX10/V-ATPase-regulated vesicular trafficking pathway that is crucial for ciliogenesis, and reveal that SNX10/V-ATPase, through the regulation of cilia formation in various organs, play an essential role during early embryonic development.
分选连接蛋白（SNXs）是一类能够结合磷酸肌醇的蛋白，其在体外能够分选多种膜蛋白，但其体内功能仍知之甚少。我们之前曾报道过，SNX10 是 SNX 家族基因中的一个独特成员，因为它在细胞中具有空泡形成活性。在本研究中，我们通过功能丧失实验来研究 SNX10 的生物学功能，并证明 SNX10 对于培养细胞中初级纤毛的形成是必需的。在斑马鱼中，SNX10 参与了 Kupffer 囊泡中的纤毛发生，对于内脏器官的左右模式形成是必需的。在机制上，SNX10 与 V-ATPase 复合物相互作用，并将其靶向到纤毛发生起始的中心体。与 SNX10 一样，V-ATPase 调节体外和体内的纤毛发生，并且与 SNX10 协同作用。我们进一步发现，SNX10 和 V-ATPase 调节 Rab8a 的纤毛运输，Rab8a 是纤毛膜延伸的关键调节因子。这些结果确定了一个由 SNX10/V-ATPase 调节的囊泡运输途径，对于纤毛发生至关重要，并表明 SNX10/V-ATPase 通过调节各种器官中的纤毛形成，在早期胚胎发育中发挥着重要作用。
