Extended Data Fig. 10: GLUT4 compartmentalizes RLRs to the plasma membrane to attenuate RLR signaling.

Viral RNA is sensed by cytosolic RIG-I and MDA5 that leads to MAVS oligomerization at the mitochondria for IFN-β production. During viral infection, GLUT4 trafficking machinery are activated—including AKT, AMPK and c-Cbl—that promote UBXN9 cleavage, thus liberating GLUT4 storage vesicle (GSVs) for surface translocation. RLRs are then sequestered to the plasma membrane by mobilized GLUT4, leading to attenuated IFN-β responses and augmented virus replication. Of note, GLUT4 can effectively tether the steady state and IFN-β-induced pool of cytosolic RLRs. The loop 6 and C terminus of GLUT4 is responsible for binding to the RLR CARD domain. Colored ‘P’ circle denotes AKT, AMPK and c-Cbl are phosphorylated after virus infection. GLUT4 storage vesicles, GSVs. Mitochondrial antiviral-signaling protein, MAVS. Caspase activation and recruitment domains, CARDs. RIG-I-like receptor, RLR.