RIG-I alarm: a molecular switch to detect invading RNA virus by the cell innate immune system
Cells are equipped with molecular sensors that can detect anomalous RNA synthesis activity occurring in the cytosol such as those resulting from the invasion by an RNA virus. RIG-I is a key sensor to detect major virus pathogens such as measles, rabies, respiratory syncytial, hepatitis C and influenza virus (see Gerlier and Lyles, for review). RIG-I is made of two CARD domains, a central helicase domain and a C terminal domain CTD. RIG-I recognizes a double stranded RNA (dsRNA) molecules with a 5’ triphosphate end. CTD essentially binds to the 5’ppp end and the helicase to dsRNA. The CARD domains are responsible for the signal transduction that leads to the activation of interferon and cytokine response responsible for raising an antiviral state and an inflammation response, respectively. The team of S. Cusack from EMBL and CNRS laboratory in Grenoble (http://www.embl.fr/) captured several snapshots of RIG-I along its activation pathway (http://www.embl.fr/aboutus/communication_outreach/media_relations/2011/111014_Grenoble/index.html). In resting state, the helicase of full length RIG-I is rather flexible with CARD2 domain bound to the helicase intermediate domain resulting in auto-inhibition, while the CTD remains mobile. Upon binding, a cognate dsRNA displaces CARD2 and binds to the helicase, a binding which is stabilized by ATP binding on the back of the helicase. This relieves the CARD domains that can now recruit the cellular factors ensuring the downstream signaling and activation of the cell innate immune response. This structural based model received first validation by site-directed mutagenesis done in collaboration by the team of D. Gerlier from INSERM U758, ENS Lyon.
- Kowalinski, E., Lunardi, T., McCarthy, A.A., Louber, J., Brunel, J., Grigorov, B., Gerlier, D. & Cusack, S. Structural basis for the activation of innate immune pattern recognition receptor RIG-I by viral RNA. Cell, 14 October 2011, 147:423-435. DOI: 10.1016/j.cell.2011.09.039, (http://f1000.com/13357266).
- Gerlier, D. & Lyles, D. Interplay between innate immunity and negative-strand RNA viruses: towards a rational model. Microbiol. Mol. Biol. Rev. 2011, p. 468–490 Vol. 75, No. 3, doi:10.1128/MMBR.00007-11
See also press English press release http://www.embl.fr/aboutus/communication_outreach/media_relations/2011/111014_Grenoble/PR14Oct11.pdf
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