Exterminate it activation key
How multiple ubiquitination sites are coordinated during RIG-I activation remains unclear. Although the importance of K63-linked ubiquitination of RIG-I is widely appreciated, the physiological significance of multisite ubiquitination in RIG-I has not been addressed. Recently, we found that optimal RIG-I activation requires conjugated K63-linked ubiquitination as a prerequisite to initiate its binding with unanchored ubiquitin chains in cell systems ( 13). Furthermore, unanchored ubiquitin chains are also reported to augment RIG-I activation signaling ( 12– 14).
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Other E3 ligases, such as MEX3C and TRIM4, were then found to play parallel roles in RIG-I activation ( 10, 11). ( 9) first demonstrated that K63-linked ubiquitination of RIG-I at Lys 172 (K172) is required for type I IFN activation. K63-linked ubiquitination plays a critical role in RIG-I activation ( 7, 8). The N terminus of RIG-I, which contains two caspase activation and recruitment domains (CARDs), transmits upstream signaling to the mitochondrial antiviral signaling (MAVS) protein for type I IFN activation ( 6). 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. 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. Experimental and mathematical modeling showed that multisite ubiquitination provides robustness in RIG-I–mediated type I interferon (IFN) signaling.
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We identified a stratified model for RIG-I amino-terminal ubiquitination, in which initiation at either Lys 164 or Lys 172 allows subsequent ubiquitination at other lysines, to trigger and amplify RIG-I activation.
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Although multiple ubiquitination sites at the amino terminus of RIG-I have been identified, their functional allocations in RIG-I activation remain elusive. The activation of retinoic acid–inducible gene I (RIG-I), an indispensable viral RNA sensor in mammals, is subtly regulated by ubiquitination.