Xian Huifang, Huang Wanming, Sun Tingzhe, Yang Shuai, Zhang Chuanxia, Wang Jun, Zhang Yuxia, Cui Jun
MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China; Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
Sci Bull (Beijing). 2021 Apr 30;66(8):794-802. doi: 10.1016/j.scib.2020.11.003. Epub 2020 Nov 9.
Ubiquitination plays a crucial role in retinoic acid-inducible gene I (RIG-I)-induced antiviral responses. However, the precise regulatory mechanisms of RIG-I activity mediated by conjugated and unanchored ubiquitin chains remain to be determined. In this study, we discovered that T55 of RIG-I was required for its binding ability for the unanchored ubiquitin chains. Experimental and mathematical analysis showed that unanchored ubiquitin chains associated with RIG-I were essential for sustained activation of type I interferon (IFN) signaling. Transcriptomics study revealed that the binding of RIG-I with unanchored ubiquitin chains additionally regulated the expression of a subset of metabolic and cell fate decision genes. Moreover, we found that ubiquitin-specific peptidase 21 (USP21) and USP3 deubiquitinate conjugated and unanchored ubiquitin chains on RIG-I respectively. Taken together, characterization of the regulation mode and functions of conjugated ubiquitination and the unconjugated ubiquitin chain-binding of RIG-I may provide means to fine-tune RIG-I-mediated type I IFN signaling.
泛素化在维甲酸诱导基因I（RIG-I）介导的抗病毒反应中起关键作用。然而，由共轭和非锚定泛素链介导的RIG-I活性的确切调控机制仍有待确定。在本研究中，我们发现RIG-I的T55位点是其与非锚定泛素链结合能力所必需的。实验和数学分析表明，与RIG-I相关的非锚定泛素链对于I型干扰素（IFN）信号的持续激活至关重要。转录组学研究显示，RIG-I与非锚定泛素链的结合还额外调节了一部分代谢和细胞命运决定基因的表达。此外，我们发现泛素特异性肽酶21（USP21）和USP3分别去除RIG-I上的共轭和非锚定泛素链。综上所述，对RIG-I共轭泛素化的调控模式和功能以及非共轭泛素链结合的表征，可能为微调RIG-I介导的I型IFN信号提供方法。
