Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth
Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth
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DOI：
10.1038/s41467-020-16696-6
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发表时间：
2020-06
影响因子：
16.6
通讯作者：
Linda Sawade;F. Grandi;Marianna Mignanelli;G. Patiño-López;K. Klinkert;F. Langa-Vives;Roberta Di Guardo;A. Echard;A. Bolino;V. Haucke
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作者：
Linda Sawade;F. Grandi;Marianna Mignanelli;G. Patiño-López;K. Klinkert;F. Langa-Vives;Roberta Di Guardo;A. Echard;A. Bolino;V. Haucke
遗传性周围神经病（IPN）代表一组广泛的病症，包括Charcot-Marie-Tooth（CMT）神经病，其特征在于主要在髓鞘、轴突或两者中产生的缺陷。近100个已鉴定的IPN/CMT基因突变导致神经病变的分子机制知之甚少。在这里，我们发现Ras相关的GTCRab 35通过与肌微管蛋白相关的磷脂酰肌醇（PI）3-磷酸酶MTMR 13和MTMR 2（由人类CMT-4 B2和B1型基因编码）形成复合物来控制髓鞘生长，并发现它下调脂质介导的mTORC 1激活，这是一种已知的关键调节髓鞘生物发生的途径。Rab 35的靶向破坏导致由PI 3-磷酸水平升高引起的mTORC 1信号传导的过度活化和体内局灶性髓鞘形成过度。磷脂酰肌醇3，5-二磷酸合成或mTORC 1信号传导的药理学抑制改善了这种表型。这些发现揭示了Rab 35通过肌微管蛋白调节脂质周转以抑制mTORC 1活性并控制髓鞘生长的关键作用。
Inherited peripheral neuropathies (IPNs) represent a broad group of disorders including Charcot-Marie-Tooth (CMT) neuropathies characterized by defects primarily arising in myelin, axons, or both. The molecular mechanisms by which mutations in nearly 100 identified IPN/CMT genes lead to neuropathies are poorly understood. Here we show that the Ras-related GTPase Rab35 controls myelin growth via complex formation with the myotubularin-related phosphatidylinositol (PI) 3-phosphatases MTMR13 and MTMR2, encoded by genes responsible for CMT-types 4B2 and B1 in humans, and found that it downregulates lipid-mediated mTORC1 activation, a pathway known to crucially regulate myelin biogenesis. Targeted disruption of Rab35 leads to hyperactivation of mTORC1 signaling caused by elevated levels of PI 3-phosphates and to focal hypermyelination in vivo. Pharmacological inhibition of phosphatidylinositol 3,5-bisphosphate synthesis or mTORC1 signaling ameliorates this phenotype. These findings reveal a crucial role for Rab35-regulated lipid turnover by myotubularins to repress mTORC1 activity and to control myelin growth.