A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis
A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis
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DOI：
10.1016/j.cell.2007.03.053
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发表时间：
2007-06-15
期刊：
影响因子：
64.5
通讯作者：
Jackson, Peter K.
中科院分区：
文献类型：
--
作者：
Nachury, Maxence V.;Loktev, Alexander V.;Jackson, Peter K.
原发纤毛功能障碍是Bardet-Biedl综合征(BBS)发病的基础，BBS是一种遗传性疾病，其症状包括肥胖、视网膜变性和肾病。然而，尽管已经鉴定了12个BBS基因，但BBS的分子基础仍然难以捉摸。在这里，我们确定了一个由七个高度保守的BBS蛋白组成的复合体。这种复合体，BBSome，定位于细胞质中的非膜性中心粒卫星，也定位于纤毛膜。有趣的是，BBSome是纤毛发生所必需的，但对于中心粒卫星功能却是必不可少的。这种纤毛形成功能部分是由Rab8 GDP/GTP交换因子介导的，该因子定位于基底体并与BBSome接触。值得注意的是，Rab8(GTP)进入初级纤毛，促进睫状膜的伸展。相反，阻止Rab8 GTP的产生阻止了细胞的调节，并产生了斑马鱼特有的BBS表型。我们的数据表明，BBS可能是由于囊泡到纤毛的运输缺陷所致。
Primary cilium dysfunction underlies the pathogenesis of Bardet-Biedl syndrome (BBS), a genetic disorder whose symptoms include obesity, retinal degeneration, and nephropathy. However, despite the identification of 12 BBS genes, the molecular basis of BBS remains elusive. Here we identify a complex composed of seven highly conserved BBS proteins. This complex, the BBSome, localizes to nonmembranous centriolar satellites in the cytoplasm but also to the membrane of the cilium. Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Strikingly, Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Conversely, preventing Rab8 GTP production blocks ciliation in cells and yields characteristic BBS phenotypes in zebrafish. Our data reveal that BBS may be caused by defects in vesicular transport to the cilium.