Japanese encephalitis virus utilizes the canonical pathway to activate NF-kappaB but it utilizes the type I interferon pathway to induce major histocompatibility complex class I expression in mouse embryonic fibroblasts.
Flaviviruses have been shown to induce cell surface expression of major histocompatibility complex class I (MHC-I) through the activation of NF-kappaB. Using IKK1(-/-), IKK2(-/-), NEMO(-/-), and IKK1(-/-) IKK2(-/-) double mutant as well as p50(-/-) RelA(-/-) cRel(-/-) triple mutant mouse embryonic fibroblasts infected with Japanese encephalitis virus (JEV), we show that this flavivirus utilizes the canonical pathway to activate NF-kappaB in an IKK2- and NEMO-, but not IKK1-, dependent manner. NF-kappaB DNA binding activity induced upon virus infection was shown to be composed of RelA:p50 dimers in these fibroblasts. Type I interferon (IFN) production was significantly decreased but not completely abolished upon virus infection in cells defective in NF-kappaB activation. In contrast, induction of classical MHC-I (class 1a) genes and their cell surface expression remained unaffected in these NF-kappaB-defective cells. However, MHC-I induction was impaired in IFNAR(-/-) cells that lack the alpha/beta IFN receptor, indicating a dominant role of type I IFNs but not NF-kappaB for the induction of MHC-I molecules by Japanese encephalitis virus. Our further analysis revealed that the residual type I IFN signaling in NF-kappaB-deficient cells is sufficient to drive MHC-I gene expression upon virus infection in mouse embryonic fibroblasts. However, NF-kappaB could indirectly regulate MHC-I expression, since JEV-induced type I IFN expression was found to be critically dependent on it.
Abraham
Sojan
S
Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
Nagaraj
Ashwini Sankrepatna
AS
Basak
Soumen
S
Manjunath
Ramanathapuram
R
D000818:Animals; D002478:Cells, Cultured; D004664:Encephalitis Virus, Japanese / Q000502:physiology*; D005347:Fibroblasts / Q000821:virology; D005805:Genes, MHC Class I / Q000235:genetics*; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
D007370:Interferon Type I; D016328:NF-kappa B