Zhang Qimin, Huang Shan, He Yan, Wang Weiwei, Tong Chao, Ma Mengru, Zhao Manyu, Yi Lian, Knobeloch Klaus-Peter, Zhang Peijing
Department of Pharmacy, Personalized Drug Therapy Key Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
National Engineering Research Center for Nanomedicine, the Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
Adv Sci (Weinh). 2025 Sep;12(34):e03865. doi: 10.1002/advs.202503865. Epub 2025 Jun 17.
The essential cytoplasmic RNA sensor Melanoma Differentiation-Associated protein 5 (MDA5) initiates type I interferons (IFNs) signaling and subsequent immune responses. However, aberrant activation of MDA5 by viral infections or gain-of-function mutations leads to severe autoimmune diseases, for most of which effective treatment is limited. Here, it is shown that inactivation of ubiquitin-specific protease 8 (USP8/UBPy) degrades the MDA5 protein, suppressing antiviral signaling and autoimmunity. It is found that viral infection modulates the AKT-dependent phosphorylation of USP8 at serine 718, which not only promotes the activation of USP8 but also enhances the association between USP8 and MDA5 and the consequent deubiquitination and stabilization of MDA5. Inactivation of USP8 specifically degrades the MDA5 protein regardless of the mutation pattern. Genetic deletion of Usp8 in mice contributes to decreased levels of type I interferons and proinflammatory cytokines. Importantly, inhibition of USP8 or AKT can effectively suppress MDA5-induced autoimmunity in Aicardi-Goutières syndrome (AGS) mice and anti-MDA5-positive dermatomyositis (DM)/systemic lupus erythematosus (SLE) patient cells. Therefore, these results highlight the critical roles of USP8 in innate antiviral immunity against RNA viruses and autoimmunity and provide a potential therapy for treating autoimmune diseases associated with MDA5.
重要的细胞质RNA传感器黑色素瘤分化相关蛋白5（MDA5）启动I型干扰素（IFN）信号传导及随后的免疫反应。然而，病毒感染或功能获得性突变导致的MDA5异常激活会引发严重的自身免疫性疾病，其中大多数疾病的有效治疗方法有限。在此研究中发现，泛素特异性蛋白酶8（USP8/UBPy）失活会降解MDA5蛋白，抑制抗病毒信号传导和自身免疫。研究发现，病毒感染可调节USP8在丝氨酸718处的AKT依赖性磷酸化，这不仅促进USP8的激活，还增强USP8与MDA5之间的结合以及随之而来的MDA5去泛素化和稳定化。无论突变模式如何，USP8失活都会特异性地降解MDA5蛋白。小鼠中Usp8的基因缺失导致I型干扰素和促炎细胞因子水平降低。重要的是，抑制USP8或AKT可有效抑制Aicardi-Goutières综合征（AGS）小鼠和抗MDA5阳性皮肌炎（DM）/系统性红斑狼疮（SLE）患者细胞中MDA5诱导的自身免疫。因此，这些结果突出了USP8在针对RNA病毒的先天性抗病毒免疫和自身免疫中的关键作用，并为治疗与MDA5相关的自身免疫性疾病提供了一种潜在的治疗方法。
