Related Experiment Video

Updated: Jun 23, 2025

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
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IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease

Nuo Chen1, Xiaoyu Wang1, Yaxin Guo1

  • 1Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, China.

Communications Biology
|June 21, 2024
PubMed

Insights

The anti-inflammatory cytokine IL-37d suppresses Rheb activity, preventing mTORC1 overactivation independently of TSC2. This finding offers a new therapeutic target for developmental disorders and liver disease.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Immunology

Background:

  • Tuberous sclerosis complex 2 (TSC2) normally inhibits Rheb to prevent mTORC1 activation.
  • Mutations in TSC genes cause mTORC1 overactivation, leading to developmental disorders and cancer.
  • Novel Rheb inhibitors are needed to control mTOR overactivation.

Purpose of the Study:

  • To investigate the potential of IL-37d as a novel Rheb inhibitor.
  • To elucidate the mechanism by which IL-37d suppresses mTORC1 signaling.
  • To evaluate the therapeutic potential of IL-37d in alcohol-induced liver disorders.

Main Methods:

  • Protein-protein interaction assays to study IL-37d and Rheb binding.
  • Cellular assays to assess mTORC1 signaling pathway activity.
  • Animal models to evaluate the efficacy of rh-IL-37d in alcohol-induced liver injury.

Main Results:

  • IL-37d binds to lysosomal Rheb and inhibits its activity, independent of TSC2.
  • IL-37d binding destabilizes Rheb-mTOR and mTOR-S6K interactions, halting mTORC1 signaling.
  • Recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide ameliorates alcohol-induced liver disorders by inhibiting the Rheb-mTORC1 axis.

Conclusions:

  • IL-37d acts as a novel Rheb suppressor, independent of TSC2, to terminate mTORC1 activation.
  • IL-37d can improve abnormal lipid metabolism in the liver.
  • IL-37d represents a potential therapeutic strategy for TSC-related disorders and alcohol-induced liver disease.

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