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 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.

Emerging Regulatory Roles of Dual-Specificity Phosphatases in Inflammatory Airway Disease

“…A similar role for DUSP1 was seen in infection of the NCI-H1299 cell line with the avian coronavirus infectious bronchitis virus, with DUSP1 siRNA treatment increasing mRNA levels of CXCL8 in response to infection [87]. This augmented cytokine expression is likely to be due to elevated MAPK activation, with increased levels of phosphorylated p38 and JNK found in RSV infected A549 cells treated with DUSP1 siRNA [88].…”

Bioinformatics analyses of significant genes, related pathways, and candidate diagnostic biomarkers and molecular targets in SARS-CoV-2/COVID-19

“…OAS1 was liable for progression of severe acute respiratory syndrome (SARS) viral infection [ Hamano et al, 2005 ], but this gene may be associated with development of SARS-CoV-2 infection. Enriched genes such as CCL4 [ Al-Afif et al, 2015 ], IFIT3 [ Ternette et al, 2011 ], CCR1 [ Miller et al, 2006 ], CXCL13 [ Chalin et al, 2018 ], CX3CR1 [ Anderson et al, 2020 ] and DUSP1 [ Robitaille et al, 2017 ] were associated with progression of respiratory syncytial virus infection, but these genes may be key for advancement of SARS-CoV-2 infection. The novel biomarkers (CARD16, MEFV (MEFV innate immunity regulator, pyrin), CYBB (cytochrome b -245 beta chain), GBP4, CARD6, CASP5, HLX (H2.0 like homeobox), IL2RA, IL2RG, IL18RAP, GZMB (granzyme B), UBE2L6, FCGR1B, TRIM38, EIF2AK2, TRIM34, KPNA5, WARS1, PIK3CG, PRKCB (protein kinase C beta), TIAM2, DOCK2, GNB4, PTPRC (protein tyrosine phosphatase receptor type C), POR (cytochrome p 450 oxidoreductase), SLC27A2, RPL21, RPL26, RPL27, RPL27A, RPL29, RPL31, RPL32, RPL34, RPL37, RPL39, RPL36A, RPLP0, RPLP1, RPLP2, RPS2, RPS3, RPS3A, RPS5, RPS7, RPS8, RPS9, RPS10, RPS14, RPS15, RPS15A, RPS16, RPS18, RPS21, RPS27, RPS28, RPS29, FAU (FAU ubiquitin like and ribosomal protein S30 fusion), RPL36, MRPL14, RPS10-NUDT3, RPL10A, RPL17-C18orf32, RPL35, RPL13A, RPL3, RPL6, RPL7, RPL7A, RPL8, RPL15, RPL19, FOS (Fos proto-oncogene, AP-1 transcription factor subunit), JUNB (JunB proto-oncogene, AP-1 transcription factor subunit), JUND (JunD proto-oncogene, AP-1 transcription factor subunit), RPS12, COX5A, UQCRC1, COX4I1, COX5B, COX6A1, COX7B, ATP5F1E, ATP6V0B, SLC25A6, SEPTIN5, UQCRQ (ubiquinol-cytochrome c reductase complex III subunit VII), CYC1, NDUFA2, NDUFA4, NDUFAB1, NDUFB2, NDUFB7, NDUFB10, NDUFC1, NDUFV1, NDUFS6, UQCR11, TUBB2A, TUBB4B, ARPC1A, ARF5, DNAI2, SSR4, PGLS (6-phosphogluconolactonase), TALDO1 and TKT (transketolase)) obtained from the pathway enrichment analysis are all may be associated in SARS-CoV-2 infection progression process, which suggesting that these novel biomarkers may serve as diagnostics biomarkers or therapeutic targets for this infection.…”

Identification of Differentially Expressed Genes and Enriched Pathways in SARS-CoV-2/ COVID-19 using Bioinformatics Analysis

“…Genes such as SOCS3 [48] and IL1A [49] were liable for progression of in uenza virus infection, but these genes may be linked with the progress of SARS-CoV-2 infection as well. Genes such as KLF6 [50], DUSP1 [51] and OLFM4 [52] were associated with the development of respiratory syncytial virus infection, but these genes may be responsible for the advancement of SARS-CoV-2 infection. IL6 was involved in the progression of SARS-CoV-2 infection [53].…”