Atlastin GTPases are required for Golgi apparatus and ER morphogenesis
Atlastin GTPases are required for Golgi apparatus and ER morphogenesis
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DOI：
10.1093/hmg/ddn046
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发表时间：
2008-06-01
影响因子：
3.5
通讯作者：
Blackstone, Craig
中科院分区：
文献类型：
--
作者：
Rismanchi, Neggy;Soderblom, Cynthia;Blackstone, Craig
遗传性痉挛性截瘫（SPG 1 -33）包括一组遗传性神经系统疾病，其主要特征是由于皮质脊髓运动神经元的长度依赖性逆行轴突病引起的下肢痉挛和无力。编码大的寡聚体GTatlastin-1的基因中的突变负责SPG 3A，一种常见的常染色体显性遗传性痉挛性截瘫。在这里，我们描述了一个家庭的人GTP酶，atlastin-2和-3，是密切相关的atlastin-1。有趣的是，虽然atlastin-1主要定位于囊泡管状复合体和顺式高尔基体池，主要在脑中，atlastin-2和-3定位于内质网（ER），并在其他组织中最丰富。使用siRNA（小干扰RNA）敲低HeLa细胞中的atlastin-2和atlastin-3水平导致高尔基体形态的破坏，并且这些高尔基体结构对布雷菲德菌素A处理保持敏感。有趣的是，缺乏GTP酶活性的SPG 3A突变体或显性负性atlastin蛋白的表达导致对ER网状化的显著抑制，表明atlastin GTP酶在ER中形成三向连接中的作用。然而，分泌途径运输评估使用水泡性口炎病毒G蛋白融合到绿色荧光蛋白（VSVG-GFP）作为报告基因是基本正常的敲除和显性负过表达条件下的所有atlastins。因此，atlastin家族的GTP酶功能突出，在ER和高尔基体形态发生，但他们似乎并不需要一般的顺行ER到高尔基体的贩运。由atlastin-1突变引起的ER和Golgi形态发生异常可能最终通过干扰皮质脊髓长运动神经元的适当膜分布或极性而成为SPG 3A的基础。
The hereditary spastic paraplegias (SPG1-33) comprise a cluster of inherited neurological disorders characterized principally by lower extremity spasticity and weakness due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Mutations in the gene encoding the large oligomeric GTPase atlastin-1 are responsible for SPG3A, a common autosomal dominant hereditary spastic paraplegia. Here we describe a family of human GTPases, atlastin-2 and -3 that are closely related to atlastin-1. Interestingly, while atlastin-1 is predominantly localized to vesicular tubular complexes and cis-Golgi cisternae, mostly in brain, atlastin-2 and -3 are localized to the endoplasmic reticulum (ER) and are most enriched in other tissues. Knockdown of atlastin-2 and -3 levels in HeLa cells using siRNA (small interfering RNA) causes disruption of Golgi morphology, and these Golgi structures remain sensitive to brefeldin A treatment. Interestingly, expression of SPG3A mutant or dominant-negative atlastin proteins lacking GTPase activity causes prominent inhibition of ER reticularization, suggesting a role for atlastin GTPases in the formation of three-way junctions in the ER. However, secretory pathway trafficking as assessed using vesicular stomatitis virus G protein fused to green fluorescent protein (VSVG-GFP) as a reporter was essentially normal in both knockdown and dominant-negative overexpression conditions for all atlastins. Thus, the atlastin family of GTPases functions prominently in both ER and Golgi morphogenesis, but they do not appear to be required generally for anterograde ER-to-Golgi trafficking. Abnormal morphogenesis of the ER and Golgi resulting from mutations in atlastin-1 may ultimately underlie SPG3A by interfering with proper membrane distribution or polarity of the long corticospinal motor neurons.