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Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production

An Addendum to this article was published on 18 December 2013

This article has been updated

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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Figure 1: RIG-I signaling is required and sufficient for IL-1β production after infection with an RNA virus.
Figure 2: RIG-I controls IL-1β production and caspase-1 activation after detecting RNA viruses.
Figure 3: MAVS and CARD9 are essential for RIG-I-induced production of IL-1β but are dispensable for inflammasome activation.
Figure 4: MAVS, CARD9 and Bcl-10 control pro-IL-1β production after RIG-I ligation.
Figure 5: RIG-I engages ASC to induce inflammasome activation.
Figure 6: RIG-I-induced inflammasome activation is independent of NLRP3.
Figure 7: Mda5 requires NLRP3 for inflammasome activation.

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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Correspondence to Jürgen Ruland.

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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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