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RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1.

ABSTRACT: The innate immune system provides an initial defense system against microbial infections and contributes to the development of adaptive immune response. Type I interferons play a pivotal role for the first line of defense against virus infections, and dendritic cells (DCs) are important sensors of pathogens responsible for priming of adaptive immune responses in lymphoid organs. Here we have investigated the role and mechanisms of activation of the MAPK pathway in innate immune responses induced by Sendai virus, a negative sense single-stranded RNA virus. Both p38 and JNK were activated in fibroblasts and DCs after infection with Sendai virus in a manner dependent on virus replication and RIG-I. Virus replication was also required for stimulation of interferon production in both cell types and interleukin-12 production in DCs. Blocking of p38 MAPK activation by the specific inhibitor SB202190 abolished the expression of these cytokines. p38 MAPK exerted its function independent of the MAPK-activated protein kinases MK2, MNK, and MSK1/2. We also observed that TRAF2 and TAK1 were essential for RIG-I-mediated activation of p38 MAPK. Interestingly, the kinase activity of p38 MAPK was required for its own phosphorylation, which was kinetically associated with TAB1 interaction. By contrast, the canonical p38 upstream kinase MKK3 was not involved in the p38-dependent response. Thus, activation of p38 MAPK by RIG-I proceeds via a TRAF2-TAK1-dependent pathway, where the enzymatic activity of the kinase plays an essential role. The p38 MAPK in turn stimulates important processes in the innate antiviral response.

SUBMITTER: Mikkelsen SS

PROVIDER: S-EPMC2667765 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1.

Mikkelsen Susie S SS Jensen Søren B SB Chiliveru Srikanth S Melchjorsen Jesper J Julkunen Ilkka I Gaestel Matthias M Arthur J Simon C JS Flavell Richard A RA Ghosh Sankar S Paludan Søren R SR

The Journal of biological chemistry 20090218 16

The innate immune system provides an initial defense system against microbial infections and contributes to the development of adaptive immune response. Type I interferons play a pivotal role for the first line of defense against virus infections, and dendritic cells (DCs) are important sensors of pathogens responsible for priming of adaptive immune responses in lymphoid organs. Here we have investigated the role and mechanisms of activation of the MAPK pathway in innate immune responses induced ...[more]

PMID: 19224920

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Project description:Rationale: Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. Methods: The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. In vitro kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. Results: HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Conclusion: Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.

Dataset Information

RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1.

Publications

RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1.

Similar Datasets

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