RelA Ser276 Phosphorylation-Coupled Lys310 Acetylation Controls Transcriptional Elongation of Inflammatory Cytokines in Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is a negative-sense single-stranded RNA virus responsible for lower respiratory tract infections (LRTIs) in humans. In experimental models of RSV LRTI, the actions of the nuclear factor B (NF-B) transcription factor mediate inflammation and pathology. We have shown that RSV replication induces a mitogen-and-stress-related kinase 1 (MSK-1) pathway that activates NF-B RelA transcriptional activity by a process involving serine phosphorylation at serine (Ser) residue 276. In this study, we examined the mechanism by which phospho-Ser276 RelA mediates expression of the NF-B-dependent gene network. RelA-deficient mouse embryonic fibroblasts (

Ataxia Telangiectasia Mutated Kinase Mediates NF-κB Serine 276 Phosphorylation and Interferon Expression via the IRF7-RIG-I Amplification Loop in Paramyxovirus Infection

“…RSV replication in airway epithelial cells is a potent trigger of intracellular and endosomal pattern recognition receptors (13)(14)(15)(16). Our work and that of others have shown that cytoplasmic viral genomic RNA is recognized initially by the cytoplasmic retinoic acid-inducible gene I (RIG-I) and later by the endosomal Toll-like receptor 3 (TLR3) (17,18), whose coordinated actions are required for an effective innate immune response (19)(20)(21).…”

“…In the case of RSV infection, RelA Ser 276 phosphorylation is mediated by the reactive oxygen species (ROS)-inducible RS6K family member MSK1 (mitogen and stress-activated kinase 1) (37). NF-B/RelA Ser 276 phosphorylation is a rate-limiting posttranslational modification necessary for p300/CBP-dependent Lys 310 acetylation and complex formation with BRD4/CDK9 positive transcriptional elongation factor (14). As a result, RelA Ser 276 is a key posttranslational modification controlling immediate early cytokine gene expression by the process of transcriptional elongation (14).…”

“…NF-B/RelA Ser 276 phosphorylation is a rate-limiting posttranslational modification necessary for p300/CBP-dependent Lys 310 acetylation and complex formation with BRD4/CDK9 positive transcriptional elongation factor (14). As a result, RelA Ser 276 is a key posttranslational modification controlling immediate early cytokine gene expression by the process of transcriptional elongation (14). Understanding the oxidative pathways controlling inducible posttranslational modification of NF-B/RelA is of obvious importance to the pathogenesis of RSV LRTI.…”

IκB Kinase ε Targets Interferon Regulatory Factor 1 in Activated T Lymphocytes

“…7A and B). RelA acetylation at Lys310 determines the recruitment of the cellular elongation factor PTEF-b by the binding of the bromodomain 4 (Brd4) protein to obtain full transcriptional processivity by RNA polymerase II (Pol II) (43,44). We speculate that IRF-1, through its ability to promote RelA acetylation at Lys310, may facilitate both PTEF-b recruitment and transcriptional elongation of the IFN-␤ and IL-8 genes.…”

Modulation of Gene Expression Regulated by the Transcription Factor NF-κB/RelA

“…Cell Culture-Human A549 pulmonary epithelial cells (American Type Culture Collection (ATCC)) were grown in F12K medium (Invitrogen) with 10% fetal bovine serum, 100 units/ml penicillin, and 100 g/ml streptomycin at 37°C in a 5% CO 2 incubator as described previously (28).…”