TY - JOUR
T1 - Distinct roles for the NF-κB RelA subunit during antiviral innate immune responses
AU - Basagoudanavar, Suresh H.
AU - Thapa, Roshan J.
AU - Nogusa, Shoko
AU - Wang, Junmei
AU - Beg, Amer A.
AU - Balachandran, Siddharth
N1 - Basagoudanavar, Suresh H Thapa, Roshan J Nogusa, Shoko Wang, Junmei Beg, Amer A Balachandran, Siddharth eng P30 CA076292/CA/NCI NIH HHS/ R01 AI059715/AI/NIAID NIH HHS/ T32 CA009035/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Virol. 2011 Mar;85(6):2599-610. doi: 10.1128/JVI.02213-10. Epub 2011 Jan 5.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Animals Cell Survival Cells, Cultured Fibroblasts/immunology/virology Gene Expression Profiling Humans Immunity, Innate Interferon-beta/metabolism Mice Mice, Inbred C57BL Mice, Knockout Transcription Factor RelA/metabolism Vesiculovirus/immunology/pathoge
UR - http://www.scopus.com/inward/record.url?scp=79952384759&partnerID=8YFLogxK
U2 - 10.1128/JVI.02213-10
DO - 10.1128/JVI.02213-10
M3 - Article
C2 - 21209118
SN - 0022-538X
VL - 85
SP - 2599
EP - 2610
JO - Journal of Virology
JF - Journal of Virology
IS - 6
ER -