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TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes

Sharon C Hook1, Alexandra Chadt2,3, Kate J Heesom1

  • 1School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, BS8 1TD, UK.

Scientific Reports
|October 22, 2020
PubMed

Insights

Researchers identified new proteins, VPS13A and VPS13C, that interact with TBC1D1 to regulate glucose transporter type 4 (GLUT4) trafficking. This discovery offers potential therapeutic targets for insulin resistance and type 2 diabetes.

Area of Science:

  • Cell biology
  • Molecular endocrinology
  • Metabolic disease research

Background:

  • Insulin resistance and type 2 diabetes are linked to impaired glucose uptake, with GLUT4 trafficking being a critical regulatory process.
  • TBC1D1 is a key protein controlling glucose uptake and GLUT4 trafficking in response to insulin and exercise.
  • Identifying TBC1D1-interacting proteins is crucial for understanding and targeting metabolic dysregulation.

Purpose of the Study:

  • To identify novel proteins that interact with TBC1D1 and regulate GLUT4 trafficking and homeostasis.
  • To investigate the role of these TBC1D1-interacting proteins in the context of insulin resistance and diabetes.

Main Methods:

  • Unbiased quantitative proteomics was employed to identify TBC1D1-interacting proteins in C2C12 myotubes.
  • Protein interactions were analyzed, focusing on associations via TBC1D1's phosphotyrosine binding (PTB) domains.
  • Gene depletion studies (VPS13A, VPS13C) were performed to assess their impact on GLUT4 levels and cell surface expression.

Main Results:

  • Proteomics identified VPS13A, VPS13C, EHBP1L1, MICAL1, and SERCA1 as TBC1D1 interactors.
  • These proteins bind to TBC1D1 via its PTB domains, independently of AMPK activation.
  • Depletion of VPS13A or VPS13C led to increased cellular and cell surface GLUT4 levels, specifically for GLUT4, upon AMPK activation.

Conclusions:

  • The TBC1D1 PTB domains act as a scaffold for various Rab regulators, including VPS13A and VPS13C.
  • VPS13 proteins play a significant role in regulating GLUT4 trafficking and cellular glucose uptake.
  • These findings highlight VPS13 proteins as potential therapeutic targets for managing insulin resistance and type 2 diabetes.

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