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Caspase-12 controls West Nile virus infection via the viral RNA receptor RIG-I

Nature Immunology volume 11, pages 912–919 (2010)Cite this article

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Abstract

Caspase-12 has been shown to negatively modulate inflammasome signaling during bacterial infection. Its function in viral immunity, however, has not been characterized. We now report an important role for caspase-12 in controlling viral infection via the pattern-recognition receptor RIG-I. After challenge with West Nile virus (WNV), caspase-12-deficient mice had greater mortality, higher viral burden and defective type I interferon response compared with those of challenged wild-type mice. In vitro studies of primary neurons and mouse embryonic fibroblasts showed that caspase-12 positively modulated the production of type I interferon by regulating E3 ubiquitin ligase TRIM25–mediated ubiquitination of RIG-I, a critical signaling event for the type I interferon response to WNV and other important viral pathogens.

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Figure 1: Casp12−/− mice are more prone to WNV encephalitis and develop exacerbated neurological symptoms.
Figure 2: Caspase-12 is required for an effective type I interferon response to WNV in vivo and in vitro.
Figure 3: Caspase-12 is important for the type I interferon response to WNV and SeV in MEFs.
Figure 4: IFN-α and IFN-β signaling is intact in Casp12−/− MEFs.
Figure 5: Caspase-12 interacts with RIG-I.
Figure 6: Caspase-12 regulates RIG-I ubiquitination.

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Acknowledgements

We thank J.F. Anderson (Connecticut Agricultural Experiment Station) for WNV, and J.U. Jung (University of Southern California) for plasmids. Supported by the National Institutes of Health (AI-055749 and AI-50031), the Howard Hughes Medical Institute (E.F.), the Northeast Biodefense Center (U54-AI057158-Lipkin to P.W.) and the Canadian Institutes for Health Research (79410 to M.S.).

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  1. Penghua Wang and Alvaro Arjona: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut, USA

    Penghua Wang, Alvaro Arjona, Yue Zhang, Hameeda Sultana, Jianfeng Dai, Long Yang & Erol Fikrig

  2. Department of Medicine, McGill University, Montreal, Quebec, Canada

    Philippe M LeBlanc, Karine Doiron & Maya Saleh

  3. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Hameeda Sultana & Erol Fikrig

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Contributions

P.W., A.A., M.S. and E.F. conceived hypotheses, analyzed data and prepared the manuscript; P.W. and A.A. designed and did experiments; Y.Z., H.S., J.D., L.Y., P.M.L. and K.D. aided in experiments; and all authors discussed the results and implications and commented on the manuscript at all stages. E.F. and M.S. contributed equally to this work.

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Correspondence to Maya Saleh or Erol Fikrig.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 262 kb)

Supplementary Video 1

Footprint-WT. Movie of wild type mouse on 5 day post i.p. infection with 1500 PFU of WNV (MOV 3617 kb)

Supplementary Video 2

Footprint-Casp12 KO. Movie of Caspase-12 knockout mouse on 5 day post i.p. infection with 1500 PFU of WNV (MOV 4826 kb)

Supplementary Video 3

Footprint-Casp1 KO. Movie of Caspase-12 knockout mouse on 5 day post i.p. infection with 1500 PFU of WNV (MOV 7610 kb)

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Wang, P., Arjona, A., Zhang, Y. et al. Caspase-12 controls West Nile virus infection via the viral RNA receptor RIG-I. Nat Immunol 11, 912–919 (2010). https://doi.org/10.1038/ni.1933

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