Gerondopoulos Andreas, Bastos Ricardo Nunes, Yoshimura Shin-Ichiro, Anderson Rachel, Carpanini Sarah, Aligianis Irene, Handley Mark T, Barr Francis A
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, England, UK.
Department of Cell Biology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
J Cell Biol. 2014 Jun 9;205(5):707-20. doi: 10.1083/jcb.201403026. Epub 2014 Jun 2.
The ancestral Rab GTPase Rab18 and both subunits of the Rab3GAP complex are mutated in the human neurological and developmental disorder Warburg Micro syndrome. Here, we demonstrate that the Rab3GAP complex is a specific Rab18 guanine nucleotide exchange factor (GEF). The Rab3GAP complex localizes to the endoplasmic reticulum (ER) and is necessary for ER targeting of Rab18. It is also sufficient to promote membrane recruitment of Rab18. Disease-associated point mutations of conserved residues in either the Rab3GAP1 (T18P and E24V) or Rab3GAP2 (R426C) subunits result in loss of the Rab18 GEF and membrane-targeting activities. Supporting the view that Rab18 activity is important for ER structure, in the absence of either Rab3GAP subunit or Rab18 function, ER tubular networks marked by reticulon 4 were disrupted, and ER sheets defined by CLIMP-63 spread out into the cell periphery. Micro syndrome is therefore a disease characterized by direct loss of Rab18 function or loss of Rab18 activation at the ER by its GEF Rab3GAP.
在人类神经和发育障碍沃伯格微综合征中，祖先的Rab GTP酶Rab18以及Rab3GAP复合物的两个亚基均发生了突变。在此，我们证明Rab3GAP复合物是一种特异性的Rab18鸟嘌呤核苷酸交换因子（GEF）。Rab3GAP复合物定位于内质网（ER），是Rab18靶向内质网所必需的。它也足以促进Rab18的膜募集。Rab3GAP1（T18P和E24V）或Rab3GAP2（R426C）亚基中保守残基的疾病相关点突变导致Rab18 GEF和膜靶向活性丧失。支持Rab18活性对内质网结构很重要这一观点的是，在缺乏Rab3GAP亚基或Rab18功能的情况下，由网质蛋白4标记的内质网管状网络被破坏，由CLIMP-63定义的内质网片层扩散到细胞周边。因此，微综合征是一种以Rab18功能直接丧失或其GEF Rab3GAP在内质网处Rab18激活丧失为特征的疾病。
