Florida Research and Innovation Center, Cleveland Clinic, Port St. Lucie, FL, USA.
FEBS J. 2024 Mar;291(6):1115-1118. doi: 10.1111/febs.17026. Epub 2023 Dec 15.
Hepatitis C virus (HCV) is a significant human pathogen that can cause a number of serious diseases including chronic inflammation of the liver, cirrhosis, and hepatocellular carcinoma. A key enzyme in the HCV life cycle is the nonstructural protein 5B (NS5B), which functions as an RNA-dependent RNA polymerase (RdRp) responsible for replicating the viral RNA genome. In their recent study, Dansako and colleagues showed that HCV NS5B induces type I interferon via activation of the RNA receptor MDA5, an activity that was dependent on the RdRp enzymatic activity but independent of viral RNA replication. Their data further indicated that the NS5B enzymes of HCV and the related GB virus-B produce cellular double-stranded RNA (dsRNA) species with potential immunostimulatory activity. These findings unveil an unconventional mechanism of activation of MDA5-mediated host immunity by viral RdRp enzymes, which is expected to spur new research directions in viral immunology.
丙型肝炎病毒（HCV）是一种重要的人类病原体，可引起多种严重疾病，包括肝脏慢性炎症、肝硬化和肝细胞癌。HCV 生命周期中的关键酶是非结构蛋白 5B（NS5B），它作为 RNA 依赖性 RNA 聚合酶（RdRp），负责复制病毒 RNA 基因组。Dansako 及其同事在最近的研究中表明，HCV NS5B 通过激活 RNA 受体 MDA5 诱导 I 型干扰素，该活性依赖于 RdRp 酶活性，但不依赖于病毒 RNA 复制。他们的数据进一步表明，HCV 和相关的 GB 病毒-B 的 NS5B 酶产生具有潜在免疫刺激活性的细胞双链 RNA（dsRNA）物质。这些发现揭示了病毒 RdRp 酶激活 MDA5 介导的宿主免疫的一种非传统机制，预计将激发病毒免疫学的新研究方向。
