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Beta-Cell Tipe1 Orchestrates Insulin Secretion and Cell Proliferation by Promoting Gαs/cAMP Signaling via USP5

Lu Ding1, Yang Sun1, Yan Liang1

  • 1Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 28, 2024
PubMed

Insights

TNF-α-induced protein 8-like 1 (Tipe1) is crucial for maintaining pancreatic beta cell function and mass. Loss of Tipe1 worsens type 2 diabetes (T2D) by impairing the Gαs/cAMP pathway, highlighting Tipe1 as a potential T2D therapeutic target.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Type 2 diabetes (T2D) is characterized by inadequate beta-cell mass and function.
  • The role of TNF-α-induced protein 8-like 1 (Tipe1) in T2D pathogenesis is largely unknown.

Purpose of the Study:

  • To investigate the role of Tipe1 in maintaining beta-cell homeostasis and its potential contribution to T2D.
  • To elucidate the molecular mechanisms by which Tipe1 regulates beta-cell function.

Main Methods:

  • Beta-cell-specific knockout of Tipe1 (Ins2-Tipe1BKO) in mouse models of diabetes (db/db and high-fat diet-induced).
  • Analysis of beta-cell mass, function, and molecular pathways involving Gαs, ubiquitination, and cAMP signaling.

Main Results:

  • Tipe1 deficiency in beta cells aggravated diabetic phenotypes in mice.
  • Tipe1 was found to enhance beta-cell mass and function by stabilizing Gαs protein levels.
  • Tipe1 inhibits K48-linked ubiquitination and degradation of Gαs via recruitment of USP5.
  • Restoration of Gαs or cAMP levels ameliorated beta-cell dysfunction in Tipe1-deficient mice.

Conclusions:

  • Tipe1 is a critical regulator of beta-cell function and homeostasis in the context of T2D.
  • The Gαs/cAMP pathway is essential for Tipe1's protective effects on beta cells.
  • Tipe1 represents a promising novel therapeutic target for T2D intervention.
Keywords:
Gαs ubiquitinationTipe1deubiquitinase USP5diabetesislet β cell

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