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

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 RSVinfected 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.Respiratory syncytial virus (RSV) belongs to the Pneumoviridae family of large enveloped negative-sense ssRNA viruses that includes important human pathogens 1,2 . RSV is a leading cause of acute lower respiratory tract infections associated with morbidity and mortality in infants, children and elderly, but also adults of all-age with a compromised immune system, cardiopulmonary diseases or following transplantation 3,4 . The capacity of the host to mount an appropriate antiviral defense aimed at limiting virus replication and spreading is critical to determine the outcome of the infection. As a consequence, the inability of the host to sustain an antiviral response leads to failure in eradicating the infection. Conversely, uncontrolled duration or intensity of the response is harmful to the host and is associated with the development of virus-associated pathogenesis, chronic inflammatory diseases and various autoimmune diseases 5,6 . Therefore, 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, but also the activation of cell death pathways, such as apoptosis, are subjected to stringent regulation by both positive and negative mechanisms 8,9 .

Novel signaling pathways regulate SARS-CoV and SARS-CoV-2 infectious disease

“…[ 54 , 55 ] DUSP1 regulates respiratory Syncytial virus and Sendai virus infection. [ 56 ] BACH1 knockdown reduces BZLF1 expression and further Epstein-Barr virus (EBV) infection. [ 57 ] BACH2 triggers viral reservoir in T regulatory cells in HIV-1 models.…”

Green Tea Polyphenols Alleviate Kidney Injury Induced by Di(2-Ethylhexyl) Phthalate in Mice

“…The biological functions of Dusp1 gene primarily focus on cell death. DUSP1 regulates ferroptosis [59], and another experiment [60] reported that DUSP1 regulates cell apoptosis and migration during the infection of respiratory syncytial and Sendai viruses.…”

Coronaviruses induce the expression of the dual specificity phosphatase DUSP1/MKP1.

“…Changes in expression of DUSP1 have been reported in association with multiple types of viral infections. These viruses include vaccinia virus, hepatitis C virus, Respiratory Syncytial Virus, Sendai Virus, and the Kaposi Sarcoma herpesvirus (KSHV) (15)(16)(17)(18). In fact DUSP1 has previously been implicated in coronavirus biology, in the case of a chicken coronavirus, infectious bronchitis virus (IBV) (19).…”