RT Journal Article SR Electronic T1 Stratified ubiquitination of RIG-I creates robust immune response and induces selective gene expression JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP e1701764 DO 10.1126/sciadv.1701764 VO 3 IS 9 A1 Xian, Huifang A1 Xie, Weihong A1 Yang, Shuai A1 Liu, Qingxiang A1 Xia, Xiaojun A1 Jin, Shouheng A1 Sun, Tingzhe A1 Cui, Jun YR 2017 UL http://advances.sciencemag.org/content/3/9/e1701764.abstract AB The activation of retinoic acid–inducible gene I (RIG-I), an indispensable viral RNA sensor in mammals, is subtly regulated by ubiquitination. Although multiple ubiquitination sites at the amino terminus of RIG-I have been identified, their functional allocations in RIG-I activation remain elusive. We identified a stratified model for RIG-I amino-terminal ubiquitination, in which initiation at either Lys164 or Lys172 allows subsequent ubiquitination at other lysines, to trigger and amplify RIG-I activation. Experimental and mathematical modeling showed that multisite ubiquitination provides robustness in RIG-I–mediated type I interferon (IFN) signaling. Furthermore, the flexibly controlled ultrasensitivity and IFN activation intensity determine the specificity of the IFN-stimulated gene transcription and manipulate cell fate in antiviral immune response. Our work demonstrates that tunable type I IFN signaling can be regulated through multisite RIG-I ubiquitination and elucidates a new paradigm for dynamic regulation in RIG-I–mediated antiviral signaling.