DUSP1 regulates apoptosis and cell migration, but not the JIP1-protected cytokine response, during Respiratory Syncytial Virus and Sendai Virus infection

Alexa C Robitaille,Anaïs Gélinas,Elise Caron,Audray Fortin,Espérance Mukawera,Damien Adam,Emmanuelle Brochiero,Nicolas Zucchini,Nathalie Grandvaux,Mélissa K Mariani

doi:10.1038/s41598-017-17689-0

Abstract

The host antiviral response involves the induction of interferons and proinflammatory cytokines, but also the activation of cell death pathways, including apoptosis, to limit viral replication and spreading. This host defense is strictly regulated to eliminate the infection while limiting tissue damage that is associated with virus pathogenesis. Post-translational modifications, most notably phosphorylation, are key regulators of the antiviral defense implying an important role of protein phosphatases. Here, we investigated the role of the dual-specificity phosphatase 1 (DUSP1) in the host defense against human respiratory syncytial virus (RSV), a pathogenic virus of the Pneumoviridae family, and Sendai virus (SeV), a model virus being developed as a vector for anti-RSV vaccine. We found that DUSP1 is upregulated before being subjected to proteasomal degradation. DUSP1 does not inhibit the antiviral response, but negatively regulates virus-induced JNK/p38 MAPK phosphorylation. Interaction with the JNK-interacting protein 1 scaffold protein prevents dephosphorylation of JNK by DUSP1, likely explaining that AP-1 activation and downstream cytokine production are protected from DUSP1 inhibition. Importantly, DUSP1 promotes SeV-induced apoptosis and suppresses cell migration in RSV-infected cells. Collectively, our data unveils a previously unrecognized selective role of DUSP1 in the regulation of tissue damage and repair during infections by RSV and SeV.

Highlights

Respiratory syncytial virus (RSV) belongs to the Pneumoviridae family of large enveloped negative-sense ssRNA viruses that includes important human pathogens[1,2]
The exact role of the Ser/Thr protein phosphatase 1 (PP1) in the antiviral response remains elusive as PP1α and PP1γ were found to dephosphorylate melanoma differentiation-associated protein 5 (MDA-5) and retinoic acid-inducible gene I (RIG-I) leading to their activation[28], while they were described to be responsible for the dephosphorylation of key C-terminal phosphoresidues of IRF3 leading to its inhibition[29]
We show that dual-specificity phosphatase 1 (DUSP1) negatively regulates p38 and JNK phosphorylation induced by Sendai virus (SeV) and respiratory syncytial virus (RSV) (Figs 3 and 4)

Summary

Introduction

Respiratory syncytial virus (RSV) belongs to the Pneumoviridae family of large enveloped negative-sense ssRNA viruses that includes important human pathogens[1,2]. These responses need to reach the ideal intensity and duration for efficient fighting of the infection while limiting tissue damage and promote tissue repair[7] To this aim, the various components of the host antiviral defense, including the transcriptional induction of interferons (IFNs) and proinflammatory cytokines and chemokines, and the activation of cell death pathways, such as apoptosis, are subjected to stringent regulation by both positive and negative mechanisms[8,9]. In response to IFNs, hundreds of interferon-stimulated genes (ISGs) are induced to limit virus replication through enhancement of virus detection and innate immune signaling, cytoskeleton remodelling, inhibition of protein translation, induction of apoptosis, amongst other antiviral functions[24,25,26] These same PRRs have been shown to activate IFN-independent cell death pathways, including apoptosis[8]. These findings point to a previously unrecognized role of DUSP1 in functions that have an impact on virus-associated tissue damage and repair

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Conclusion