Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming
Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming
复制标题
DOI：
10.1126/sciadv.aay1109
复制
发表时间：
2020-03-01
期刊：
影响因子：
13.6
通讯作者：
Beling, Antje
中科院分区：
文献类型：
--
作者：
Kespohl, Meike;Bredow, Clara;Beling, Antje
用ISG 15（ISGylation）修饰的蛋白质代表主要的I型IFN诱导的抗微生物系统。然而，ISGylation的共同作用机制和物种特异性方面仍然不明确和有争议。我们使用多相柯萨奇病毒B3（CV）感染模型，第一波导致肝脏损伤，随后第二波导致心脏损伤。这项研究表明，ISGylation设置非造血细胞进入耐药状态，是不可或缺的CV控制，这是通过协同活性的ISG 15抗病毒IFIT 1/3蛋白。在改变能量需求的同时，ISG 15还在感染期间适应肝脏代谢。鸟枪蛋白质组学与代谢网络建模相结合，揭示了ISG 15增加了肝细胞的氧化能力并促进了肝细胞的再生。缺乏ISG 15特异性蛋白酶USP 18活性的细胞表现出对临床相关CV菌株的抗性增加，因此表明通过抑制USP 18来稳定ISG化可以用于CV相关的人类病理学。
Protein modification with ISG15 (ISGylation) represents a major type I IFN-induced antimicrobial system. Common mechanisms of action and species-specific aspects of ISGylation, however, are still ill defined and controversial. We used a multiphasic coxsackievirus B3 (CV) infection model with a first wave resulting in hepatic injury of the liver, followed by a second wave culminating in cardiac damage. This study shows that ISGylation sets nonhematopoietic cells into a resistant state, being indispensable for CV control, which is accomplished by synergistic activity of ISG15 on antiviral IFIT1/3 proteins. Concurrent with altered energy demands, ISG15 also adapts liver metabolism during infection. Shotgun proteomics, in combination with metabolic network modeling, revealed that ISG15 increases the oxidative capacity and promotes gluconeogenesis in liver cells. Cells lacking the activity of the ISG1 5specific protease USP18 exhibit increased resistance to clinically relevant CV strains, therefore suggesting that stabilizing ISGylation by inhibiting USP18 could be exploited for CV-associated human pathologies.