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dc.contributor.authorGranja, Aitor G.-
dc.contributor.authorNogal París, María Luisa-
dc.contributor.authorHurtado, Carolina-
dc.contributor.authorAguila, Carmen del-
dc.contributor.authorCarrascosa, Ángel L.-
dc.contributor.authorSalas, María Luisa-
dc.contributor.authorFresno, Manuel-
dc.contributor.authorRevilla Novella, Yolanda-
dc.identifier.citationThe Journal of Immunology, 2006, 176: 451-462en_US
dc.descriptionArticle available at http://www.jimmunol.org/cgi/content/abstract/176/1/451en_US
dc.description.abstractAfrican swine fever virus (ASFV) is able to inhibit TNF--induced gene expression through the synthesis of A238L protein. This was shown by the use of deletion mutants lacking the A238L gene from the Vero cell-adapted Ba71V ASFV strain and from the virulent isolate E70. To further analyze the molecular mechanism by which the viral gene controls TNF-, we have used Jurkat cells stably transfected with the viral gene to identify the TNF- regulatory elements involved in the induction of the gene after stimulation with PMA and calcium ionophore. We have thus identified the cAMP-responsive element and 3 sites on the TNF- promoter as the responsible of the gene activation, and demonstrate that A238L inhibits TNF- expression through these DNA binding sites. This inhibition was partially reverted by overexpression of the transcriptional factors NF-AT, NF-B, and c-Jun. Furthermore, we present evidence that A238L inhibits the activation of TNF- by modulating NF-B, NF-AT, and c-Jun trans activation through a mechanism that involves CREB binding protein/p300 function, because overexpression of these transcriptional coactivators recovers TNF- promoter activity. In addition, we show that A238L is a nuclear protein that binds to the cyclic AMP-responsive element/3 complex, thus displacing the CREB binding protein/p300 coactivators. Taken together, these results establish a novel mechanism in the control of TNF- gene expression by a viral protein that could represent an efficient strategy used by ASFV to evade the innate immune responseen_US
dc.description.sponsorshipThis work was supported by grants from Ministerio de Educación y Ciencia (BFU2004-00298/BMC), the Wellcome Trust (075813/C/04/z), and by an institutional grant from the Fundación Ramón Areces. C.H. was a fellow from Fundación Ramón Areces.en_US
dc.format.extent3436629 bytes-
dc.publisherAmerican Association of Immunologistsen_US
dc.subjectA238L proteinen_US
dc.titleThe Viral Protein A238L Inhibits TNF-α Expression through a CBP/p300 Transcriptional Coactivators Pathwayen_US
dc.description.peerreviewedPeer revieweden_US
dc.contributor.funderMinisterio de Educación y Ciencia (España)-
dc.contributor.funderWellcome Trust-
dc.contributor.funderFundación Ramón Areces-
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