RIG-I, a cytoplasmic viral RNA sensor, is crucial for innate antiviral immune responses; however, there are controversies about RIG-I regulatory mechanism by several ubiquitin ligases and LGP2. Our genetic study revealed that the RIPLET ubiquitin ligase was a general activating factor for RIG-I signaling, whereas another ubiquitin ligase, TRIM25, activated RIG-I in a cell-type-specific manner. These RIPLET and TRIM25 functions were modulated by accessory factors, such as ZCCH3C and NLRP12. Interestingly, we found an additional role of RIPLET in innate immune responses. RIPLET induced delayed polyubiquitination of LGP, resulting in the attenuation of excessive cytokine expression at the late phase. Moreover, RIPLET was involved in the innate immune responses against SARS-CoV-2 infection, a cause of the recent COVID-19 pandemic. Our data indicate that RIPLET fine-tunes innate immune responses via polyubiquitination of RIG-I and LGP2 against virus infection, including SARS-CoV-2.

中文翻译：

---

泛素连接酶RIPLET介导RIG-1和LGP2的多泛素化并调节对SARS-CoV-2感染的先天免疫应答

RIG-I是一种细胞质病毒RNA传感器，对于先天的抗病毒免疫反应至关重要。但是，一些泛素连接酶和LGP2对RIG-I调控机制存在争议。我们的遗传研究表明，RIPLET泛素连接酶是RIG-I信号传导的一般激活因子，而另一种泛素连接酶TRIM25以细胞类型特异性方式激活RIG-I。这些RIPLET和TRIM25功能由辅助因素（例如ZCCH3C和NLRP12）调制。有趣的是，我们发现了RIPLET在先天免疫反应中的其他作用。RIPLET诱导了LGP的延迟多聚泛素化，导致晚期细胞因子过度表达的减弱。此外，RIPLET参与了针对SARS-CoV-2感染的先天免疫反应，SARS-CoV-2感染是近期COVID-19大流行的原因。