Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth

Nat Commun. 2020 Jun 5;11(1):2835. doi: 10.1038/s41467-020-16696-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / pathology
  • Down-Regulation
  • Gene Knock-In Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lipid Metabolism / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice, Transgenic
  • Mutation
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology
  • Primary Cell Culture
  • Protein Tyrosine Phosphatases, Non-Receptor / antagonists & inhibitors
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*


  • Mechanistic Target of Rapamycin Complex 1
  • MTMR2 protein, human
  • Mtmr2 protein, mouse
  • Protein Tyrosine Phosphatases, Non-Receptor
  • SBF2 protein, human
  • RAB35 protein, human
  • Rab35 protein, mouse
  • rab GTP-Binding Proteins

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 4B1
  • Charcot-Marie-Tooth disease, Type 4B2