Abstract
Interleukin 1β (IL-1β) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-κB and subsequent processing of pro-IL-1β by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus–induced production of IL-1β are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus–induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-κB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9–Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain RNA viruses.
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Change history
15 May 2013
In 2010 we reported in Nature Immunology how the sensing of cytosolic RNA triggers the generation of mature interleukin 1β (IL-1β; Poeck et al., Nat. Immunol. 11, 63–69 (2010)). We demonstrated that ligation of the RNA helicase RIG-I triggered the adaptor CARD9 downstream of the signaling adaptor MAVS (IPS-1) to induce the transcription factor NF-κB for the generation of pro-IL-1β and in parallel activated caspase-1 for the generation of mature IL-1β. We presented data that indicated similar generation of pro-IL-1β and IL-1β in wild-type bone marrow–derived dendritic cells (BMDCs) and BMDCs deficient in CARD9 or the adaptor Bcl-10 after transfection of the synthetic DNA poly(dA:dT) (Fig. 3c (right) and Fig. 4c,e,f). However, additional experiments in our laboratory have shown that CARD9- or Bcl-10-deficient BMDCs have impaired production of pro-IL-1β and IL-1β not only after sensing of RNA but also after the transfection of poly(dA:dT). We speculate that a particular aliquot of poly(dA:dT) used during the preparation of our study published in 2010 might have been contaminated with lipopolysaccharide or some other CARD9-independent trigger of the innate immune system. Still, the central conclusions of that manuscript (that RIG-I signals via CARD9 and the inflammasome to control IL-1β) remain unchanged and have been confirmed by multiple independent laboratories. Nevertheless, we would like to correct the idea that CARD9- or Bcl-10-deficient cells have normal IL-1β responses to the transfection of poly(dA:dT).
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Acknowledgements
We thank J. Tschopp (University of Lausanne) for critical reading of the manuscript, discussions and NLRP3-deficient, ASC-deficient and MAVS-deficient mice and plasmids; and A. Krug (Technical University of Munich) for EMCV. This work includes parts of a thesis by M.B. at the University of Munich. Supported by Bundesministerium für Bildung und Forschung Biofuture (G.H.), Deutsche Forschungsgemeinschaft (SFB704, SFB670, SFB832 and KFO177 to G.H.; Sonderforschungsbereiche to S.E., V.H. and J.R.; Graduiertenkolleg 1202 to M.B.; and RO 2525/3–1 to S.R.), the Center for Integrated Protein Science Munich (S.E.), the European Research Council (V.H.) and Deutsche Krebshilfe (J.R.).
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H.P., M.B., O.G., G.H., V.H. and J.R. designed the research; H.P., M.B., O.G., K.F., S.R., N.H., M.R. and M.S. did experiments; W.B., H.K., S.A. and S.I. contributed critical reagents; H.P., M.B., O.G., S.R., S.E., C.P., V.H., G.H. and J.R. analyzed results; H.P. and M.B. prepared the figures; and H.P., M.B., O.G., G.H. and J.R. wrote the paper.
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Poeck, H., Bscheider, M., Gross, O. et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production. Nat Immunol 11, 63–69 (2010). https://doi.org/10.1038/ni.1824
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DOI: https://doi.org/10.1038/ni.1824
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