BBS蛋白的核心复合物与GTP酶Rab8协同作用，以促进纤毛膜生物发生。

A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.

作者信息

Nachury Maxence V, Loktev Alexander V, Zhang Qihong, Westlake Christopher J, Peränen Johan, Merdes Andreas, Slusarski Diane C, Scheller Richard H, Bazan J Fernando, Sheffield Val C, Jackson Peter K

机构信息

Genentech, Inc., South San Francisco, CA 94080, USA.

出版信息

Cell. 2007 Jun 15;129(6):1201-13. doi: 10.1016/j.cell.2007.03.053.

DOI:10.1016/j.cell.2007.03.053

PMID:17574030

Abstract

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.

摘要

原发性纤毛功能障碍是巴德-比德尔综合征（BBS）发病机制的基础，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，尽管已鉴定出12个BBS基因，但BBS的分子基础仍不清楚。在此，我们鉴定出一个由7种高度保守的BBS蛋白组成的复合物。这个复合物，即BBSome，定位于细胞质中的非膜性中心粒卫星，但也定位于纤毛膜。有趣的是，BBSome是纤毛发生所必需的，但对于中心粒卫星功能是可有可无的。这种纤毛发生功能部分由定位于基体并与BBSome接触的Rab8 GDP/GTP交换因子介导。引人注目的是，Rab8（GTP）进入原发性纤毛并促进纤毛膜的延伸。相反，阻止Rab8（GTP）的产生会阻断细胞中的纤毛形成，并在斑马鱼中产生典型的BBS表型。我们的数据表明，BBS可能是由向纤毛的囊泡运输缺陷引起的。