Disease-related myotubularins function in endocytic traffic in Caenorhabditis elegans
Disease-related myotubularins function in endocytic traffic in Caenorhabditis elegans
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DOI：
10.1091/mbc.e03-08-0605
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发表时间：
2004-01-01
影响因子：
3.3
通讯作者：
Fares, H
中科院分区：
文献类型：
--
作者：
Dang, H;Li, Z;Fares, H
MTM1、MTMR2和SBF2属于一个被称为肌管蛋白的蛋白质家族。X连锁肌管性肌病是一种严重的先天性疾病，其特征是新生男性出现肌张力减退和全身肌肉无力，由MTM1突变引起（拉波特等人，1996年）。夏科 - 马里 - 图思病4B1型和4B2型分别是由MTMR2（博利诺等人，2000年）和SBF2/MTMR13（森德雷克等人，2003年）突变引起的严重脱髓鞘神经病。尽管已知几种肌管蛋白可调节细胞内磷酸肌醇 - 磷酸水平，但对于这些疾病患者中存在缺陷的实际细胞过程知之甚少。线虫MTM - 6和MTM - 9（属于两个亚组的肌管蛋白）的突变会扰乱磷酸肌醇3 - 磷酸的定位，并阻断秀丽隐杆线虫体腔细胞的内吞作用。我们证明MTM - 6和MTM - 9作为一个复合物的一部分发挥作用，以调节涉及Arf6 GTP酶的内吞途径，并且我们确定了MTM - 6活性所需的蛋白质结构域。
MTM1, MTMR2, and SBF2 belong to a family of proteins called the myotubularins. X-linked myotubular myopathy, a severe congenital disorder characterized by hypotonia and generalized muscle weakness in newborn males, is caused by mutations in MTM1 (Laporte et al., 1996). Charcot-Marie-Tooth types 4131 and 4132 are severe demyelinating neuropathies caused by mutations in MTMR2 (Bolino et al., 2000) and SBF2/MTMR13 (Senderek et al., 2003), respectively. Although several myotubularins are known to regulate phosphoinositide-phosphate levels in cells, little is known about the actual cellular process that is defective in patients with these diseases. Mutations in worm MTM-6 and MTM-9, myotubularins belonging to two subgroups, disorganize phosphoinositide 3-phosphate localization and block endocytosis in the coelomocytes of Caenorhabditis elegans. We demonstrate that MTM-6 and MTM-9 function as part of a complex to regulate an endocytic pathway that involves the Arf6 GTPase, and we define protein domains required for MTM-6 activity.