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Stability of tuberous sclerosis complex 2 is controlled by methylation at R1457 and R1459

Seishu Gen1, Yu Matsumoto1, Ken-Ichi Kobayashi1

  • 1Laboratory of Nutritional Biochemistry, Department of Agricultural Chemistry, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo, 156-8502, Japan.

Scientific Reports
|December 4, 2020
PubMed

Insights

Tuberous sclerosis complex 2 (TSC2) stability is regulated by novel methylation. Protein arginine methyltransferase 1 (PRMT1) methylates TSC2, impacting its phosphorylation and stability, crucial for cell growth regulation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Tuberous sclerosis complex 2 (TSC2) mutations cause tuberous sclerosis complex disease.
  • TSC2 forms a complex with TSC1 to inhibit cell growth by inactivating mTORC1.
  • TSC2 activity is primarily regulated by phosphorylation, but other mechanisms exist.

Purpose of the Study:

  • To investigate novel posttranslational modifications regulating TSC2.
  • To identify the specific methylation sites and the enzyme responsible for TSC2 methylation.
  • To determine the functional impact of TSC2 methylation on its stability and activity.

Main Methods:

  • Mass spectrometry to identify methylation sites.
  • Site-directed mutagenesis to alter specific arginine residues.
  • Western blotting to assess protein levels and phosphorylation status.
  • Co-immunoprecipitation assays to study protein interactions.

Main Results:

  • TSC2 is methylated at arginine residues R1457 and R1459 by PRMT1.
  • PRMT1-mediated methylation affects TSC2 phosphorylation at T1462 by Akt.
  • Methylation at R1457 and R1459 is essential for TSC2 protein stability.
  • This methylation pathway influences the TSC2-TSC1 complex activity.

Conclusions:

  • PRMT1-mediated methylation represents a novel regulatory mechanism for TSC2.
  • Methylation is critical for maintaining TSC2 stability and proper cellular function.
  • These findings reveal a new layer of posttranslational control over the TSC2 pathway, impacting tuberous sclerosis complex disease.

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