The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is trapped at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 translocation, sequestration of RLRs and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.

细胞质 RIG-I 样受体 （RLR） 识别病毒 RNA 并启动先天抗病毒免疫。RLR 信号转导还通过葡萄糖转运蛋白 （GLUT） 触发糖酵解重编程，葡萄糖转运蛋白在抗病毒免疫中的作用难以捉摸。在这里，我们揭示了胰岛素反应性 GLUT4 抑制 RLR 信号传导，而与脂肪和肌肉组织中的葡萄糖摄取无关。在稳态下，GLUT4 被泛素调节 X 结构域 9 （UBXN9， TUG） 困在高尔基体基质上。RNA 病毒感染后，GLUT4 被释放并易位到细胞表面，在那里它在空间上分离了大量胞质 RLR，阻止它们激活 IFN β反应。UBXN9 缺失提示组成型 GLUT4 易位、RLR 隔离和抗病毒免疫减弱，而 GLUT4 缺失增强 RLR 信号传导。值得注意的是，GLUT4 表达降低与以干扰素反应过度活跃为特征的人类炎症性肌病独特相关。总体而言，我们的结果表明一个非经典 UBXN9-GLUT4 轴，它通过胞质溶质 RLR 的质膜栓系来控制抗病毒免疫。