Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Department of Immunology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Cell Rep. 2019 Aug 20;28(8):1961-1970.e4. doi: 10.1016/j.celrep.2019.07.081.
Excessive innate immune response is harmful to the host, and aberrant activation of the cytoplasmic viral RNA sensors RIG-I and MDA5 leads to autoimmune disorders. ZNF598 is an E3 ubiquitin ligase involved in the ribosome quality control pathway. It is also involved in the suppression of interferon (IFN)-stimulated gene (ISG) expression; however, its underlying mechanism is unclear. In this study, we show that ZNF598 is a negative regulator of the RIG-I-mediated signaling pathway, and endogenous ZNF598 protein binds to RIG-I. ZNF598 ubiquitin ligase activity is dispensable for the suppression of RIG-I signaling. Instead, ZNF598 delivers a ubiquitin-like protein FAT10 to the RIG-I protein, resulting in the inhibition of RIG-I polyubiquitination, which is required for triggering downstream signaling to produce type I IFN. Moreover, ZNF598-mediated suppression is abrogated by FAT10 knockout. Our data elucidate the mechanism by which ZNF598 inhibits RIG-I-mediated innate immune response.
过度的先天免疫反应对宿主是有害的，细胞质病毒 RNA 传感器 RIG-I 和 MDA5 的异常激活会导致自身免疫紊乱。ZNF598 是一种参与核糖体质量控制途径的 E3 泛素连接酶。它还参与干扰素 (IFN) 刺激基因 (ISG) 表达的抑制；然而，其潜在机制尚不清楚。在这项研究中，我们表明 ZNF598 是 RIG-I 介导的信号通路的负调节剂，内源性 ZNF598 蛋白与 RIG-I 结合。ZNF598 泛素连接酶活性对于抑制 RIG-I 信号是可有可无的。相反，ZNF598 将一种类泛素蛋白 FAT10 递送到 RIG-I 蛋白上，从而抑制 RIG-I 的多泛素化，这对于触发下游信号以产生 I 型 IFN 是必需的。此外，FAT10 敲除会消除 ZNF598 介导的抑制作用。我们的数据阐明了 ZNF598 抑制 RIG-I 介导的先天免疫反应的机制。
