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Sci Rep. 2016 Jul 8;6:29263. doi: 10.1038/srep29263.

A Hierarchical Mechanism of RIG-I Ubiquitination Provides Sensitivity, Robustness and Synergy in Antiviral Immune Responses.

Sun X1,2,3, Xian H2, Tian S2, Sun T4, Qin Y5, Zhang S5, Cui J2,6.

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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.
School of Life Sciences, AnQing Normal University, AnQing, 246011, China.
School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.


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.

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