Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta.
Respiratory syncytial virus (RSV) is the etiological agent of acute respiratory diseases, such as bronchiolitis and pneumonia. The exacerbated production of proinflammatory cytokines and chemokines in the airways in response to RSV is an important pillar in the development of these pathologies. As such, a keen understanding of the mechanisms that modulate the inflammatory response during RSV infection is of pivotal importance to developing effective treatment. The NF-kappaB transcription factor is a major regulator of proinflammatory cytokine and chemokine genes. However, RSV-mediated activation of NF-kappaB is far from characterized. We recently demonstrated that aside from the well-characterized IkappaBalpha phosphorylation and degradation, the phosphorylation of p65 at Ser536 is an essential event regulating the RSV-mediated NF-kappaB-dependent promoter transactivation. In the present study, using small interfering RNA and pharmacological inhibitors, we now demonstrate that RSV sensing by the RIG-I cytoplasmic receptor triggers a signaling cascade involving the MAVS and TRAF6 adaptors that ultimately leads to p65ser536 phosphorylation by the IKKbeta kinase. In a previous study, we highlighted a critical role of the NOX2-containing NADPH oxidase enzyme as an upstream regulator of both the IkappaBalphaSer32 and p65Ser536 in human airway epithelial cells. Here, we demonstrate that inhibition of NOX2 significantly decreases IKKbeta activation. Taken together, our data identify a new RIG-I/MAVS/TRAF6/IKKbeta/p65Ser536 pathway placed under the control of NOX2, thus characterizing a novel regulatory pathway involved in NF-kappaB-driven proinflammatory response in the context of RSV infection.
Yoboua
Fabrice
F
Centre de recherche du CHUM-Hôpital St Luc, 264 René Levesque-Est, PEA 311, Montréal, Quebec H2X 1P1, Canada.
Martel
Alexis
A
Duval
Annick
A
Mukawera
Espérance
E
Grandvaux
Nathalie
N
D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; D012694:Serine; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D051550:I-kappa B Kinase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
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