Regulation of Inducible Nitric Oxide Synthase Expression by Viral A238L- Mediated Inhibition of p65/RelA Acetylation and p300 Transactivation.
Uncontrolled generation of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) can cause damage to host cells and inflammation, two undesirable events for virus spreading. African swine fever virus (ASFV) infection regulates iNOS- induced gene expression through the synthesis of the A238L virus protein. We here explored the role of A238L, an NF-kappaB and NFAT inhibitor, in the regulation of iNOS transcription in macrophages. NO production and iNOS mRNA and protein levels as well as iNOS promoter activity after lipopolysaccharide (LPS)-gamma interferon (IFN-gamma) treatment were down-regulated both during ASFV infection and in Raw 264.7 cells stably expressing the viral protein. Overexpression of p300, but not of a histone acetyltransferase (HAT) defective mutant, reverted the A238L- mediated inhibition of both basal and LPS-IFN-gamma- induced iNOS promoter activity. Following stimulation with LPS-IFN-gamma, p65 and p300 interaction was abolished in Raw-A238L cells. Expression of A238L also inhibited p65/relA and p300 binding to the distal NF-kappaB sequence of the iNOS promoter together with p65 acetylation. Finally, A238L abrogated p300 transactivation mediated by a GAL4-p300 construction. These results provide evidence for an unique viral mechanism involved in transcriptional regulation of iNOS gene expression.[1]References
- Regulation of Inducible Nitric Oxide Synthase Expression by Viral A238L-Mediated Inhibition of p65/RelA Acetylation and p300 Transactivation. Granja, A.G., Sabina, P., Salas, M.L., Fresno, M., Revilla, Y. J. Virol. (2006) [Pubmed]
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