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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.

Author information

1
Zhong-shan School of Medicine, Sun Yat-sen University, Guangzhou 510089, China.
2
School of Life Science, Sun Yat-sen University, Guangzhou, 510275, China.
3
School of Mathematical and Computational Science, Sun Yat-sen University, Guangzhou, 510000, China.
4
School of Life Sciences, AnQing Normal University, AnQing, 246011, China.
5
School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
6
Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.

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.

PMID:
27387525
PMCID:
PMC4937349
DOI:
10.1038/srep29263
[Indexed for MEDLINE]
Free PMC Article

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