2. Academic Validation
  3. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy

TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy

  • Sci Adv. 2025 Oct 10;11(41):eadw4153. doi: 10.1126/sciadv.adw4153.
Elena Levi-D'Ancona 1 2,  Emily M Walker 1,  Jie Zhu 1,  Yamei Deng 3,  Vaibhav Sidarala 1,  Ava M Stendahl 1,  Emma C Reck 1,  Belle A Henry-Kanarek 1 2,  Anne C Lietzke 1 4,  Biaoxin Chai 1,  Mabelle B Pasmooij 1,  Dre L Hubers 1,  Venkatesha Basrur 5,  Sankar Ghosh 6,  Linsey Stiles 7 8,  Alexey I Nesvizhskii 3 5,  Orian S Shirihai 7 8,  Scott A Soleimanpour 1 9 10
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.
  • 2 Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • 4 Graduate Program in Pharmacology, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 6 Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, NY, New York, USA.
  • 7 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
  • 8 Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 9 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 10 VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
PMID: 41061082 DOI: 10.1126/sciadv.adw4153
Abstract

Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin Ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of Mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for Insulin secretion, mitochondrial respiration, and Mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) Mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) Mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated Mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated Mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.

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