Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213.
Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213.
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DOI：
10.1038/srep16161
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发表时间：
2015-11-04
影响因子：
4.6
通讯作者：
Nagata K
中科院分区：
文献类型：
--
作者：
Kotani Y;Morito D;Yamazaki S;Ogino K;Kawakami K;Takashima S;Hirata H;Nagata K
Mysterin（也称为 RNF213）是一种巨大的细胞内蛋白，具有两个 AAA+ ATP 酶模块和一个环指泛素连接酶结构域。 Mysterin 最初被分离为隐源性脑血管疾病烟雾病的重要危险因素，并被发现参与斑马鱼的生理性血管生成。然而，尽管神秘蛋白在动物组织中普遍表达，但神秘蛋白在血管以外的功能和生理意义仍然很大程度上未知。在这项研究中，我们对斑马鱼幼虫中的神秘蛋白直系同源物进行了反义介导的抑制，结果发现，神秘蛋白缺陷的幼虫表现出快速肌原纤维显着减少和初级运动神经元投射不成熟，导致严重的运动缺陷。 Mysterin 表达的快速肌肉特异性恢复消除了这些表型，有趣的是，Mysterin 的 AAA+ ATP 酶和泛素连接酶活性对于正确的快速肌肉形成是不可或缺的，这证明了 Mysterin 及其酶活性在斑马鱼神经肌肉调节中的重要作用。
Mysterin (also known as RNF213) is a huge intracellular protein with two AAA+ ATPase modules and a RING finger ubiquitin ligase domain. Mysterin was originally isolated as a significant risk factor for the cryptogenic cerebrovascular disorder moyamoya disease, and was found to be involved in physiological angiogenesis in zebrafish. However, the function and the physiological significance of mysterin in other than blood vessels remain largely unknown, although mysterin is ubiquitously expressed in animal tissues. In this study, we performed antisense-mediated suppression of a mysterin orthologue in zebrafish larvae and revealed that mysterin-deficient larvae showed significant reduction in fast myofibrils and immature projection of primary motoneurons, leading to severe motor deficits. Fast muscle-specific restoration of mysterin expression cancelled these phenotypes, and interestingly both AAA+ ATPase and ubiquitin ligase activities of mysterin were indispensable for proper fast muscle formation, demonstrating an essential role of mysterin and its enzymatic activities in the neuromuscular regulation in zebrafish.