Research Alert
Abstract ID: 1167
Newswise — 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 of these inflammatory immune responses. Here, we reveal a novel mechanism of immunometabolic regulation of RLR signaling by the glucose transporter 4 (GLUT4). In addition to its canonical role in maintaining organismal glucose homeostasis, GLUT4 attenuates innate immune signaling through sequestering RLRs into the plasma membrane. Translocation of GLUT4 from intracellular compartments to the plasma membrane is tightly regulated by UBXN9, a ubiquitin-domain containing protein (UBXN). Disruption of UBXN9 releases GLUT4, suppresses RLR signaling/IFN responses and enhances viral replication, while genetic ablation of GLUT4 improves antiviral immunity. Strikingly, these distinct phenotypes are independent of glycolysis, but dictated by the mobilization of GLUT4 to the plasma membrane. Further, GLUT4 colocalizes with RIG-I after insulin treatment (which stimulates GLUT4 trafficking) or viral infection to blunt RLR activation. Fine-tuning of this UBXN9-GLUT4 axis is critical for antiviral immunity, but dysregulation of these components may underlie inflammatory myopathies that are characterized by a hyperactive RLR-IFN pathway. Together, this study reveals a novel link between GLUTs and cytosolic immune sensors, and underscores the intersection of vesicular trafficking, glucose metabolism and antiviral immunity.
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