Unanchored ubiquitin chain sustains RIG-I-induced interferon-I activation and controls selective gene expression

Huifang Xian; Wanming Huang; Tingzhe Sun; Shuai Yang; Chuanxia Zhang; Jun Wang; Yuxia Zhang; Jun Cui

doi:10.1016/j.scib.2020.11.003

Unanchored ubiquitin chain sustains RIG-I-induced interferon-I activation and controls selective gene expression

Sci Bull (Beijing). 2021 Apr 30;66(8):794-802. doi: 10.1016/j.scib.2020.11.003. Epub 2020 Nov 9.

Authors

Huifang Xian¹, Wanming Huang², Tingzhe Sun³, Shuai Yang⁴, Chuanxia Zhang⁴, Jun Wang², Yuxia Zhang², Jun Cui⁵

Affiliations

¹ 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.
² Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
³ School of Life Sciences, Anqing Normal University, Anqing 246133, China.
⁴ MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
⁵ MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: cuij5@mail.sysu.edu.cn.

PMID: 36654136
DOI: 10.1016/j.scib.2020.11.003

Abstract

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.

Keywords: Antiviral immunity; Cellular homeostasis; RIG-I; Type I interferon; Ubiquitination; Unanchored ubiquitin chains.