期刊
SCIENTIFIC REPORTS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep29263
关键词
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资金
- National Key Basic Research Program of China [2015CB859800, 2014CB910800]
- National Natural Science Foundation of China [31522018, 31400714, 61503419]
- Guangdong Natural Science Funds for Distinguished Young Scholar [S2013050014772]
- Guangdong Innovative Research Team Program [2011Y035]
- Guangdong Nature Science Foundation [2014A030310355, 2016A030313234]
- Fundamental Research Funds for the Central Universities [15lgjc02]
- Training Program for Outstanding Young Teachers in Higher Education Institutions of Guangdong Province [YQ2015001]
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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