title: A Hierarchical Mechanism of RIG-I Ubiquitination Provides Sensitivity, Robustness and Synergy in Antiviral Immune Responses.
abstract: RIG-I is an essential receptor in the initiation of the type I interferon (IFN) signaling pathway upon viral infection. Although K63-linked ubiquitination plays an important role in RIG-I activation, the optimal modulation of conjugated and unanchored ubiquitination of RIG-I as well as its functional implications remains unclear. In this study, we determined that, in contrast to the RIG-I CARD domain, full-length RIG-I must undergo K63-linked ubiquitination at multiple sites to reach full activity. A systems biology approach was designed based on experiments using full-length RIG-I. Model selection for 7 candidate mechanisms of RIG-I ubiquitination inferred a hierarchical architecture of the RIG-I ubiquitination mode, which was then experimentally validated. Compared with other mechanisms, the selected hierarchical mechanism exhibited superior sensitivity and robustness in RIG-I-induced type I IFN activation. Furthermore, our model analysis and experimental data revealed that TRIM4 and TRIM25 exhibited dose-dependent synergism. These results demonstrated that the hierarchical mechanism of multi-site/type ubiquitination of RIG-I provides an efficient, robust and optimal synergistic regulatory module in antiviral immune responses.
authors.affiliation: Zhong-shan School of Medicine, Sun Yat-sen University, Guangzhou 510089, China.|School of Life Science, Sun Yat-sen University, Guangzhou, 510275, China.|School of Mathematical and Computational Science, Sun Yat-sen University, Guangzhou, 510000, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Sun
authors.affiliation: School of Life Science, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Xian
authors.affiliation: School of Life Science, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Tian
authors.affiliation: School of Life Sciences, AnQing Normal University, AnQing, 246011, China.
authors.forename: Tingzhe
authors.initials: T
authors.lastname: Sun
authors.affiliation: School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Qin
authors.affiliation: School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
authors.forename: Shoutao
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Life Science, Sun Yat-sen University, Guangzhou, 510275, China.|Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cui
mesh_terms: D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D057809:HEK293 Cells; D006801:Humans; D008962:Models, Theoretical; D011971:Receptors, Immunologic; D054875:Ubiquitination; D014780:Viruses / Q000276:immunology*
chemical_list: D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58