Degradation of nuclear factor kappa B during foot-and-mouth disease virus infection.
We have previously shown that the leader proteinase (L(pro)) of foot-and-mouth disease virus (FMDV) interferes with the innate immune response by blocking the translation of interferon (IFN) protein and by reducing the immediate-early induction of beta IFN mRNA and IFN-stimulated genes. Here, we report that L(pro) regulates the activity of nuclear factor kappaB (NF-kappaB). Analysis of NF-kappaB-dependent reporter gene expression in BHK-21 cells demonstrated that infection with wild-type (WT) virus has an inhibitory effect compared to infection with a genetically engineered mutant lacking the leader coding region. The expression of endogenous NF-kappaB-dependent genes tumor necrosis factor alpha and RANTES is also reduced in WT virus-infected primary porcine cells. This inhibitory effect is neither the result of a decrease in the level of the mRNA of p65/RelA, a subunit of NF-kappaB, nor a block on the nuclear translocation of p65/RelA, but instead appears to be a consequence of the degradation of accumulated p65/RelA. Viral L(pro) is localized to the nucleus of infected cells, and there is a correlation between the translocation of L(pro) and the decrease in the amount of nuclear p65/RelA. By using a recombinant cardiovirus expressing L(pro), we demonstrate that the disappearance of p65/RelA takes place in the absence of any other FMDV product. The observation that L(pro) disrupts the integrity of NF-kappaB suggests a global mechanism by which FMDV antagonizes the cellular innate immune and inflammatory responses to viral infection.
de Los Santos
Teresa
T
Plum Island Animal Disease Center, ARS, NAA, USDA, P.O. Box 848, Greenport, NY 11944, USA.
Diaz-San Segundo
Fayna
F
Grubman
Marvin J
MJ
D000818:Animals; D019677:Artificial Gene Fusion; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D006224:Cricetinae; D010450:Endopeptidases / Q000378:metabolism*; D029544:Foot-and-Mouth Disease Virus / Q000276:immunology*; D017353:Gene Deletion; D015870:Gene Expression; D017930:Genes, Reporter; D008156:Luciferases / Q000096:biosynthesis; D013552:Swine; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018946:Chemokine CCL5; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D010450:Endopeptidases; C088747:leader proteinase, foot-and-mouth disease virus