Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Peking Union Medical College, Chengdu, Sichuan 610052, PR China.
Int J Biochem Cell Biol. 2011 Oct;43(10):1427-31. doi: 10.1016/j.biocel.2011.06.006. Epub 2011 Jun 16.
The ISG15/USP18 pathway modulates cellular functions and is important for the host innate immune response to chronic viral infections such as Hepatitis C Virus (HCV). Interferon stimulated gene 15 (ISG15) was the first ubiquitin-like protein modifier identified. As in ubiquitination, ISG15 conjugates to target proteins (ISGylation) through the sequential enzymatic action of activating E1, conjugating E2, and ligating E3 enzymes. ISGylation modulates signal transduction pathways and host anti-viral response. The ISGylation process is reversible through the action of an ISG15 protease, USP18. Ubiquitin-like specific protease 18 (USP18) has functions that are both ISG15-dependent and ISG15-independent; the importance of the ISG15/USP18 pathway to chronic HCV infection is illustrated by the consistent finding of increased levels of ISG15 and USP18 in the liver tissue of patients who do not respond to interferon-based treatments. Mechanistically, HCV seems to exploit the ISG15/USP18 pathway to promote viral replication and evade innate anti-viral immune responses.
ISG15/USP18 通路调节细胞功能，对于宿主固有免疫对慢性病毒感染（如丙型肝炎病毒）的反应非常重要。干扰素刺激基因 15（ISG15）是第一个被鉴定的泛素样蛋白修饰物。与泛素化一样，ISG15 通过激活 E1、连接 E2 和连接 E3 酶的顺序酶促作用与靶蛋白（ISGylation）缀合。ISGylation 调节信号转导途径和宿主抗病毒反应。ISG15 蛋白酶 USP18 的作用使 ISGylation 过程具有可逆性。泛素样特异性蛋白酶 18（USP18）具有依赖和不依赖 ISG15 的功能；ISG15/USP18 通路对慢性 HCV 感染的重要性体现在干扰素治疗反应不佳的患者肝组织中 ISG15 和 USP18 水平持续升高的一致发现中。从机制上讲，丙型肝炎病毒似乎利用 ISG15/USP18 通路来促进病毒复制并逃避固有抗病毒免疫反应。
