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

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.