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Mitochondria-localized β-actin is essential for priming innate antiviral immune signaling by regulating IRF3 protein stability

Cellular & Molecular Immunology volume 16, pages 837–840 (2019)Cite this article

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Antiviral innate immunity acts as a defensive barrier to viral infection in both immune and nonimmune cells. The viral nucleic acids present in the cytoplasm after viral replication can activate sensors such as the RIG-I-like receptors RIG-I and MDA5 or the cytosolic DNA sensor cGAS to initiate signaling transduction.1 Activation of this signaling cascade leads to phosphorylation of the protein kinase TBK1, which in turn phosphorylates and activates the transcription factor IRF3 to upregulate type-I interferons.2 The production of the type-I interferons IFN-α and IFN-β induces the expression of interferon-stimulated genes (ISGs) that suppress viral replication.3 The stability of IRF3 is essential for sustained antiviral responses,4 and altered mitochondrial function can affect antiviral immune signaling.5 However, whether mitochondrial defects affect IRF3 protein stability remains unclear. In this study, we found that the mitochondrial pool of β-actin, which is essential for mitochondrial quality and membrane potential, is required for the maintenance of IRF3 stability and the activation of antiviral immune responses.

To confirm defects in the activation of antiviral immune responses, we treated WT and KO cells with the viral nucleoside analogs poly(I:C) and poly(dA-dT). The induction of the type-I interferons Ifna4 and Ifnb1 and the chemokine Cxcl10 was significantly impaired in KO cells following treatment with both nucleoside analogs (Fig. 1f, g). RNA-seq analysis showed that the overall induction of ISGs was largely impaired in KO cells stimulated with poly(dA-dT) (Fig. 1h). Gene ontology enrichment analysis further showed that multiple processes related to defense against viral infection were enriched in genes downregulated in KO cells stimulated by poly(dA-dT) compared to their levels in WT cells (Supplementary information, Fig. S2a). Apart from the upregulation of type-I interferons and ISGs, antiviral signaling activation can also lead to the upregulation of sensors and transcription factors in the antiviral response pathways in a positive feedback loop.6 The upregulation of many of these sensors and transcription factors was also impaired in poly(dA-dT)-stimulated KO cells compared to their expression in WT cells (Supplementary information, Fig. S2b–e). Similar results were observed when poly(I:C)-stimulated KO cells were compared to WT cells (Supplementary information, Fig. S3a–d and Fig. S4a). In addition, the induction of proapoptotic genes (Trail, Xaf1, Casp4) known to be upregulated by poly(I:C)7 was suppressed in KO cells (Supplementary information, Fig. S4b). Taken together, our data reveal the globally impaired induction of antiviral response genes in KO cells upon the activation of antiviral signaling by viral mimics.

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Acknowledgements

This work was supported by grants provided by New York University Abu Dhabi as well as grants from the Swedish Research Council (Vetenskapsrådet) and the Swedish Cancer Society (Cancerfonden) to PP. We thank the NYU Abu Dhabi Center for Genomics and Systems Biology, particularly Marc Arnoux and Mehar Sultana, for technical help and the Core Technology Platform Resources. We appreciate the computational platform provided by the NYUAD HPC team and are especially thankful to Nizar Drou for technical help.

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Authors and Affiliations

  1. Science Division, Biology Program, New York University Abu Dhabi (NYUAD), P.O. Box 129188, Abu Dhabi, United Arab Emirates

    Xin Xie, Martin Endara-Coll, Raza Mahmood, Robertas Jankauskas, Tamara Gjorgjieva & Piergiorgio Percipalle

  2. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91, Stockholm, Sweden

    Martin Endara-Coll & Piergiorgio Percipalle

  3. New York University Center for Genomics and Systems Biology, NYU, New York, NY, USA

    Raza Mahmood

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  1. Xin Xie
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XX and PP conceived the project and designed the experiments. XX, MEC, RM, RJ, and TG performed the experiments. XX and PP analyzed the data and wrote the manuscript.

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Correspondence to Piergiorgio Percipalle.

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Xie, X., Endara-Coll, M., Mahmood, R. et al. Mitochondria-localized β-actin is essential for priming innate antiviral immune signaling by regulating IRF3 protein stability. Cell Mol Immunol 16, 837–840 (2019). https://doi.org/10.1038/s41423-019-0269-2

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