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The Viral Protein A238L Inhibits TNF-α Expression through a CBP/p300 Transcriptional Coactivators Pathway

AuthorsGranja, Aitor G. ; Nogal París, María Luisa ; Hurtado, Carolina ; Aguila, Carmen del; Carrascosa, Ángel L.; Salas, María Luisa; Fresno, Manuel ; Revilla Novella, Yolanda
A238L protein
Issue DateJan-2006
PublisherAmerican Association of Immunologists
CitationThe Journal of Immunology, 2006, 176: 451-462
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 response
DescriptionArticle available at http://www.jimmunol.org/cgi/content/abstract/176/1/451
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