A238L inhibits NFAT, NFkappaB and c-Jun activation through blocking the PKC-theta-mediated up-regulation of the amino terminal transactivation domain of p300. Running title: A238L inhibits p300 amino terminal transactivation domain

The transcriptional coactivators CBP and p300 regulate inducible transcription in multiple cellular processes and during the establishment of inflammatory and immune response. Several viruses have been shown to interfere with CBP/p300 function, modulating their transcriptional activity. Here we report that the viral protein A238L interacts with the amino terminal region of p300 inhibiting the acetylation and transcriptional activation of NFAT, NFκB and c-Jun in stimulated human T cells. We demonstrate that A238L modulates the autoacetylation of p300 without altering its intrinsic histone acetyl transferase activity. Furthermore, we show that the molecular mechanism of the inhibition executed by the viral protein is carried out through blocking PKC-p300 interaction in the amino terminal transactivation domain of the coactivator. Moreover, we have found that serine 384, within the CH1 domain, is essential for the full transcriptional activation of the coactivator, showing, for the first time, a PKC-θ-mediated up-regulation of p300. Finally, we have demonstrated that A238L prevents the binding of PKC-θ to the amino terminal transactivation domain of p300, blocking its transcriptional activity. These findings provide new strategies to develop therapies potentially useful in the control of disorders related to p300 deregulation. Abbreviations: Footnote (3)