Hu Junjie, Shibata Yoko, Zhu Peng-Peng, Voss Christiane, Rismanchi Neggy, Prinz William A, Rapoport Tom A, Blackstone Craig
Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Cell. 2009 Aug 7;138(3):549-61. doi: 10.1016/j.cell.2009.05.025.
The endoplasmic reticulum (ER) consists of tubules that are shaped by the reticulons and DP1/Yop1p, but how the tubules form an interconnected network is unknown. Here, we show that mammalian atlastins, which are dynamin-like, integral membrane GTPases, interact with the tubule-shaping proteins. The atlastins localize to the tubular ER and are required for proper network formation in vivo and in vitro. Depletion of the atlastins or overexpression of dominant-negative forms inhibits tubule interconnections. The Sey1p GTPase in S. cerevisiae is likely a functional ortholog of the atlastins; it shares the same signature motifs and membrane topology and interacts genetically and physically with the tubule-shaping proteins. Cells simultaneously lacking Sey1p and a tubule-shaping protein have ER morphology defects. These results indicate that formation of the tubular ER network depends on conserved dynamin-like GTPases. Since atlastin-1 mutations cause a common form of hereditary spastic paraplegia, we suggest ER-shaping defects as a neuropathogenic mechanism.
内质网（ER）由由网质蛋白和DP1/Yop1p塑造形状的小管组成，但这些小管如何形成相互连接的网络尚不清楚。在此，我们表明，哺乳动物atlastin蛋白属于发动蛋白样的整合膜GTP酶，可与塑造小管的蛋白质相互作用。atlastin蛋白定位于内质网小管，是体内和体外形成正常网络所必需的。atlastin蛋白的缺失或显性负性形式的过表达会抑制小管的相互连接。酿酒酵母中的Sey1p GTP酶可能是atlastin蛋白的功能同源物；它具有相同的特征基序和膜拓扑结构，并在遗传和物理上与塑造小管的蛋白质相互作用。同时缺乏Sey1p和一种塑造小管蛋白质的细胞具有内质网形态缺陷。这些结果表明，内质网小管网络的形成依赖于保守的发动蛋白样GTP酶。由于atlastin-1突变会导致一种常见的遗传性痉挛性截瘫，我们提出内质网塑造缺陷是一种神经致病机制。
