title: Distinct roles for the NF-kappa B RelA subunit during antiviral innate immune responses.
abstract: Production of type I interferons (IFNs; prominently, IFN-α/β) following virus infection is a pivotal antiviral innate immune response in higher vertebrates. The synthesis of IFN-β proceeds via the virus-induced assembly of the transcription factors IRF-3/7, ATF-2/c-Jun, and NF-κB on the ifnβ promoter. Surprisingly, recent data indicate that the NF-κB subunit RelA is not essential for virus-stimulated ifnβ expression. Here, we show that RelA instead sustains autocrine IFN-β signaling prior to infection. In the absence of RelA, virus infection results in significantly delayed ifnβ induction and consequently defective secondary antiviral gene expression. While RelA is not required for ifnβ expression after infection, it is nonetheless essential for fully one-fourth of double-stranded RNA (dsRNA)-activated genes, including several mediators of inflammation and immune cell recruitment. Further, RelA directly regulates a small subset of interferon-stimulated genes (ISGs). Finally, RelA also protects cells from dsRNA-triggered RIP1-dependent programmed necrosis. Taken together, our findings suggest distinct roles for RelA in antiviral innate immunity: RelA maintains autocrine IFN-β signaling in uninfected cells, facilitates inflammatory and adaptive immune responses following infection, and promotes infected-cell survival during this process.
authors.affiliation: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Room 224, Reimann Building, 333 Cottman Ave., Philadelphia, PA 19111, USA.
authors.forename: Suresh H
authors.initials: SH
authors.lastname: Basagoudanavar
authors.forename: Roshan J
authors.initials: RJ
authors.lastname: Thapa
authors.forename: Shoko
authors.initials: S
authors.lastname: Nogusa
authors.forename: Junmei
authors.initials: J
authors.lastname: Wang
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051996:Transcription Factor RelA / Q000378:metabolism*; D018116:Vesiculovirus / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: D051996:Transcription Factor RelA; D016899:Interferon-beta