The glucose transporter GLUT4 tethers RIG-I-like receptors to suppress antiviral immunity

Abstract The current dogma of RIG-I-like receptor (RLR) regulation states that dysregulated interferon (IFN) production is predominantly repressed by reversible posttranslational modifications (e.g., ubiquitination). However, RLR activation has profound outcomes on cellular metabolism, which governs the nature these inflammatory immune responses. Here, we reveal a novel mechanism immunometabolic signaling glucose transporter 4 (GLUT4). In addition to its canonical role in maintaining organismal homeostasis, GLUT4 attenuates innate through sequestering RLRs into plasma membrane. Translocation from intracellular compartments membrane tightly regulated UBXN9, ubiquitin-domain containing protein (UBXN). Disruption UBXN9 releases GLUT4, suppresses signaling/IFN responses and enhances viral replication, while genetic ablation improves antiviral immunity. Strikingly, distinct phenotypes are independent glycolysis, but dictated mobilization Further, colocalizes with RIG-I after insulin treatment (which stimulates trafficking) or infection blunt activation. Fine-tuning this UBXN9-GLUT4 axis critical for immunity, dysregulation components may underlie myopathies characterized hyperactive RLR-IFN pathway. Together, study reveals link between GLUTs cytosolic sensors, underscores intersection vesicular trafficking, metabolism Supported grants NIH (NIH R01AI132526, R21AI155820)