Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model - Archive ouverte HAL Access content directly
Journal Articles Proceedings of the National Academy of Sciences Year : 2022

Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model

Paula Samsó
  • Function : Author
Philipp A. Koch
  • Function : Author
York Posor
  • Function : Author
Wen-Ting Lo
  • Function : Author
Hassane Belabed
  • Function : Author
Marc Nazare
  • Function : Author
Volker Haucke
  • Function : Author

Abstract

X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies caused by mutations in the phosphoinositide 3-phosphatase MTM1. Loss of MTM1 function is associated with muscle fiber defects characterized by impaired localization of β-integrins and other components of focal adhesions. Here we show that defective focal adhesions and reduced active β-integrin surface levels in a cellular model of XLCNM are rescued by loss of phosphatidylinositiol 3-kinase C2β (PI3KC2β) function. Inactivation of the Mtm1 gene impaired myoblast differentiation into myotubes and resulted in reduced surface levels of active β1-integrins as well as corresponding defects in focal adhesions. These phenotypes were rescued by concomitant genetic loss of Pik3c2b or pharmacological inhibition of PI3KC2β activity. We further demonstrate that a hitherto unknown role of PI3KC2β in the endocytic trafficking of active β1-integrins rather than rescue of phosphatidylinositol 3-phosphate levels underlies the ability of Pik3c2b to act as a genetic modifier of cellular XLCNM phenotypes. Our findings reveal a crucial antagonistic function of MTM1 and PI3KC2β in the control of active β-integrin surface levels, thereby providing a molecular mechanism for the adhesion and myofiber defects observed in XLCNM. They further suggest specific pharmacological inhibition of PI3KC2β catalysis as a viable treatment option for XLCNM patients.
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Dates and versions

hal-04217633 , version 1 (25-09-2023)

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Paula Samsó, Philipp A. Koch, York Posor, Wen-Ting Lo, Hassane Belabed, et al.. Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model. Proceedings of the National Academy of Sciences, 2022, 119 (40), ⟨10.1073/pnas.2202236119⟩. ⟨hal-04217633⟩
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