DUSP1 promotes apoptosis and suppresses cell migration, while leaving the JIP1-protected cytokine production intact, during paramyxovirus infection.

Paramyxoviruses include several pathogenic viruses, including respiratory syncytial virus (RSV). The cell autonomous antiviral response and proinflammatory cytokine secretion is key to limit viral spreading and orchestrate the subsequent immune response. This host defense must be strictly regulated to ensure a response of appropriate intensity and duration to eliminate the infection while limiting tissue damage that is associated with virus pathogenesis. Activation of the innate immune response is mainly dependent on signaling pathways leading to activation of the transcription factors NF-κB, IRF3 and AP-1. The activation and termination of the host antiviral defense is heavily regulated by post-translational modifications, most notably phosphorylation, implying that protein phosphatases are key negative regulators. Here, we investigated the role of the dual-specificity phosphatase 1 (DUSP1) in the regulation of the host defense against RSV and Sendai virus (SeV). We found that DUSP1 is upregulated during early SeV and RSV infections of A549 cells before being subjected to proteasomal degradation at later time points. We demonstrate that DUSP1 does not inhibit the cell autonomous antiviral response, but negatively regulates virus-induced JNK/p38 MAPK phosphorylation. Importantly, we found that interaction with the JNK-interacting protein (JIP) 1 scaffold protein protects a pool of JNK involved in AP-1 and cytokine production, from inhibition by DUSP1. Rather, DUSP1 promotes apoptosis, independently of JNK/p38 inhibition, and suppresses cell migration. Collectively, our data unveil a previously unrecognized selective role of DUSP1 in the regulation of functions associated with tissue damage and repair during paramyxovirus infections.