NF-kappa B RelA subunit is crucial for early IFN-beta expression and resistance to RNA virus replication.
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-kappaB transcription factors. Although NF-kappaB activation and association with the IFN-beta promoter after RNA virus infection is well documented, our previous work showed that, surprisingly, NF-kappaB is not essential for IFN-beta gene expression. Thus, the actual function of NF-kappaB 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-kappaB 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 ~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-kappaB 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.
Wang
Junmei
J
Department of Immunology, Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
Basagoudanavar
Suresh H
SH
Wang
Xingyu
X
Hopewell
Emily
E
Albrecht
Randy
R
García-Sastre
Adolfo
A
Balachandran
Siddharth
S
Beg
Amer A
AA
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D009522:Newcastle disease virus / Q000276:immunology* / Q000502:physiology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology* / Q000502:physiology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
D052002:NF-kappa B p50 Subunit; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D016899:Interferon-beta