title: 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.
authors.affiliation: Institute of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark.
authors.forename: Susie S
authors.initials: SS
authors.lastname: Mikkelsen
authors.forename: Søren B
authors.initials: SB
authors.lastname: Jensen
authors.forename: Srikanth
authors.initials: S
authors.lastname: Chiliveru
authors.forename: Jesper
authors.initials: J
authors.lastname: Melchjorsen
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D007113:Immunity, Innate / Q000502:physiology; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D029082:Sendai virus / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D007372:Interferons; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D047992:TNF Receptor-Associated Factor 2; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse; C503356:Ddx58 protein, mouse