美国康涅狄格大学Penghua Wang等研究人员合作发现，UBXN9调控GLUT4介导的RIG-I样受体及信号的空间限制。这一研究成果于2024年11月20日在线发表在国际学术期刊《自然—免疫学》上。

研究人员揭示了胰岛素响应的葡萄糖转运蛋白4（GLUT4）在脂肪和肌肉组织中独立于葡萄糖摄取而抑制RIG-I样受体（RLR）信号的机制。在稳态下，GLUT4被泛素调控X域9（UBXN9，也称TUG）捕获在高尔基基质中。

在RNA病毒感染后，GLUT4被释放并转运到细胞表面，在此处与胞质中的RLR形成空间隔离，阻止其激活IFN-β反应。UBXN9的缺失导致GLUT4持续转运、RLR的隔离以及抗病毒免疫的减弱，而GLUT4的缺失则增强了RLR信号。

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性肌病特异性相关。总体而言，该研究揭示了一个非经典的UBXN9-GLUT4轴，通过胞质RLR的质膜锚定来调控抗病毒免疫。

研究人员表示，胞质中的RLR能够识别病毒RNA并启动先天抗病毒免疫。RLR信号还通过GLUT触发糖酵解重编程，但GLUT在抗病毒免疫中的作用尚不清楚。

附：英文原文

Title: UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling

Author: Harrison, Andrew G., Yang, Duomeng, Cahoon, Jason G., Geng, Tingting, Cao, Ziming, Karginov, Timofey A., Hu, Youjia, Li, Xin, Chiari, Conner C., Qyang, Yibing, Vella, Anthony T., Fan, Zhichao, Vanaja, Sivapriya Kailasan, Rathinam, Vijay A., Witczak, Carol A., Bogan, Jonathan S., Wang, Penghua

Issue&Volume: 2024-11-20

Abstract: 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.

DOI: 10.1038/s41590-024-02004-7

Source: https://www.nature.com/articles/s41590-024-02004-7