Volume 4 Issue 2
Feb.  2013
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Miao Feng, Zhanyu Ding, Liang Xu, Liangliang Kong, Wenjia Wang, Shi Jiao, Zhubing Shi, Mark I. Greene, Yao Cong, Zhaocai Zhou. Structural and biochemical studies of RIG-I antiviral signaling[J]. Protein&Cell, 2013, 4(2): 142-154. doi: 10.1007/s13238-012-2088-4
Citation: Miao Feng, Zhanyu Ding, Liang Xu, Liangliang Kong, Wenjia Wang, Shi Jiao, Zhubing Shi, Mark I. Greene, Yao Cong, Zhaocai Zhou. Structural and biochemical studies of RIG-I antiviral signaling[J]. Protein&Cell, 2013, 4(2): 142-154. doi: 10.1007/s13238-012-2088-4

Structural and biochemical studies of RIG-I antiviral signaling

doi: 10.1007/s13238-012-2088-4
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This work was supported by the National Basic Research Program (973 Program) (Nos.2010CB529701 and 2012CB910204), the National Natural Science Foundation of China (Grant Nos. 10979005 and 30970566), and the Science and Technology Commission of Shanghai Municipality (11JC14140000).

  • Received Date: 2012-08-23
  • Rev Recd Date: 2012-11-29
  • Retinoic acid-inducible gene I (RIG-I) is an important pattern recognition receptor that detects viral RNA and triggers the production of type-I interferons through the downstream adaptor MAVS (also called IPS-1, CARDIF, or VISA). A series of structural studies have elaborated some of the mechanisms of dsRNA recognition and activation of RIG-I. Recent studies have proposed that K63-linked ubiquitination of, or unanchored K63-linked polyubiquitin binding to RIG-I positively regulates MAVS-mediated antiviral signaling. Conversely phosphorylation of RIG-I appears to play an inhibitory role in controlling RIG-I antiviral signal transduction. Here we performed a combined structural and biochemical study to further define the regulatory features of RIG-I signaling. ATP and dsRNA binding triggered dimerization of RIG-I with conformational rearrangements of the tandem CARD domains. Full length RIG-I appeared to form a complex with dsRNA in a 2:2 molar ratio. Compared with the previously reported crystal structures of RIG-I in inactive state, our electron microscopic structure of full length RIG-I in complex with blunt-ended dsRNA, for the first time, revealed an exposed active conformation of the CARD domains. Moreover, we found that purified recombinant RIG-I proteins could bind to the CARD domain of MAVS independently of dsRNA, while S8E and T170E phosphorylation-mimicking mutants of RIG-I were defective in binding E3 ligase TRIM25, unanchored K63-linked polyubiquitin, and MAVS regardless of dsRNA. These findings suggested that phosphorylation of RIG inhibited downstream signaling by impairing RIG-I binding with polyubiquitin and its interaction with MAVS.
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