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Wang JM , Basagoudanavar SH , Wang XY , Hopewell E , Albrecht R , Garcia-Sastre A , Balachandran S , Beg AA
NF-kappa B RelA Subunit Is Crucial for Early IFN-beta Expression and Resistance to RNA Virus Replication
Journal of Immunology. 2010 Aug;185(3) :1720-1729
PMCID: PMC2910841   
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RNA virus infection results in expression of type 1 IFNs, especially IFN-alpha/beta, which play a crucial role in host antivirus responses. Type 1 IFNs are induced in a cell type-specific manner through TLR and RIG-I-like receptor pathways, both of which activate IFN regulatory factors (IRFs) and NF-kappa B transcription factors. Although NF-kappa B activation and association with the IFN-beta promoter after RNA virus infection is well documented, our previous work showed that, surprisingly, NF-kappa B is not essential for IFN-beta gene expression. Thus, the actual function of NF-kappa B in IFN-beta expression and virus replication is not clear. In this study, we found Newcastle disease virus and vesicular stomatitis virus replication is enhanced in mouse embryonic fibroblasts (MEFs) lacking the NF-kappa B RelA subunit. Increased virus replication was traced to a specific requirement for RelA in early virus-induced IFN-beta expression. At these time points, when IFN-beta expression is similar to 100-fold less than peak levels, impaired IFN-beta production delayed IFN-induced gene expression, resulting in increased virus replication in RelA(-/-) MEFs. Importantly, our results show that RelA requirement is crucial only when IRF3 activation is low. Thus, high levels of activated IRF3 expression are sufficient for induction of IFN-beta in RelA(-/-) MEFs, transcriptional synergism with the coactivator CREB-binding protein, and rescue of susceptibility to virus. Together, these findings indicate that NF-kappa B RelA is not crucial for regulating overall IFN-beta production, as previously believed; instead, RelA is specifically required only during a key early phase after virus infection, which substantially impacts the host response to virus infection. The Journal of Immunology, 2010, 185: 1720-1729.
Wang, Junmei Basagoudanavar, Suresh H. Wang, Xingyu Hopewell, Emily Albrecht, Randy Garcia-Sastre, Adolfo Balachandran, Siddharth Beg, Amer A. Amer assoc immunologists Bethesda 629ei