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Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection

Abstract

During the last few decades, the global incidence of dengue virus (DENV) has increased dramatically, and it is now endemic in more than 100 countries. To establish a productive infection in humans, DENV uses different strategies to inhibit or avoid the host innate immune system. Several DENV proteins have been shown to strategically target crucial components of the type I interferon system. Here, we report that the DENV NS2B protease cofactor targets the DNA sensor cyclic GMP-AMP synthase (cGAS) for lysosomal degradation to avoid the detection of mitochondrial DNA during infection. Such degradation subsequently results in the inhibition of type I interferon production in the infected cell. Our data demonstrate a mechanism by which cGAS senses cellular damage upon DENV infection.

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Figure 1: cGAS is degraded during DENV infection.
Figure 2: DENV protease complex counteracts the cGAS/STING pathway.
Figure 3: NS2B protease cofactor degrades cGAS in an autophagy–lysosome-dependent mechanism.
Figure 4: DENV protease complex and its components counteract the cGAS/STING pathway.
Figure 5: cGAS restricts DENV replication.
Figure 6: cGAS binds mitochondrial DNA (mtDNA) during DENV infection.

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Acknowledgements

The authors thank A. Gamarnik and J. Ashour for critical discussions and input, R. Fenutria-Aumesquet for help with the statistical analysis and R. Sebra and G. Deikus for DNA sequencing. This work was supported by NIH/NIAID grants R01AI073450 and 1R21AI116022 (to A.F.-S.), 1U19AI118610 (to A.F.-S. and A.G.-S.) and a DARPA (Prophecy) grant HR0011-11-C-0094 (to A.F.-S.). J.P.-S. is supported in part by PREP grant R25GM64118 from the NIH/NIGMS. L.C.F.M. is supported by NIH-NIGMS grant R01 GM113886. V.S. is partially supported by NIH-NIAID grants R01 AI089246 and P01 AI090935. C.F.B. is supported by NIH/NIAID grant no. AI109945.

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S.A. and A.F.-S. conceived and designed the experiments. S.A., P.L., M.T.S.-A., A.M.M., J.P., F.L., T.Z., J.P.-S. and L.G.W. performed the experiments. A.C.F., S.T., D.B.-R., L.C.F.M., V.S., C.F.B. and A.G.-S. contributed reagents, materials and analysis tools for experiments. A.S. and B.G. carried out SMRT sequencing data analysis. S.A. and A.F.-S. analysed the data. S.A. and A.F.-S. wrote the paper.

Corresponding authors

Correspondence to Sebastian Aguirre or Ana Fernandez-Sesma.

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The authors declare no competing financial interests.

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Aguirre, S., Luthra, P., Sanchez-Aparicio, M. et al. Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection. Nat Microbiol 2, 17037 (2017). https://doi.org/10.1038/nmicrobiol.2017.37

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