287-OR: Traf6 Directs a Noncanonical Role for Innate Immune Signaling in Pancreatic ß-Cells

Innate immune signaling links diverse intracellular pathways in eukaryotic cells, from inflammation to metabolism as well as host defense. In immune cells, mitochondria act as docking sites for innate immune signaling pathways, including those downstream of toll-like receptors (TLRs), whose activation by inflammatory signals contribute to mitochondrial damage. The importance of innate immune signaling in β-cells, however, has been vexing. Deletion of TLRs enhances β-cell mass following diet-induced obesity (DIO), while loss of downstream TLR signaling adaptors impairs β-cell function. Moreover, the regulatory relationships between innate immune signaling and mitochondrial quality control responses to mitochondrial damage are unclear. Here, we observe that the E3 ubiquitin ligase Traf6, which is central to the transmission of TLR-dependent innate immune signals to induce inflammation, surprisingly promotes glucose homeostasis following metainflammatory stress. We generated β-cell specific Traf6 knockout mice (Traf6^Δβ), which were euglycemic at baseline, yet developed glucose intolerance and decreased glucose-stimulated insulin secretion following DIO. Islets from HFD-fed Traf6^Δβ mice exhibit increased mitochondrial mass, abnormal mitochondrial ultrastructure, and impaired mitochondrial respiration and mitophagy flux. We also observed that Traf6 translocates to the mitochondria during metabolic stress. Interestingly, metabolic defects in Traf6^Δβ mice were completely rescued by concomitant deletion of the mitophagy initiator Parkin, indicating a novel and unexpected importance for Traf6 to tune β-cell mitochondrial quality control. Thus, Traf6 links β-cell stress responses with control of mitophagy, revealing a non-canonical role for innate immune signaling in mitochondrial health.