A238L inhibits NF-ATc2, NF-kappa B, and c-Jun activation through a novel mechanism involving protein kinase C-theta-mediated up-regulation of the amino-terminal transactivation domain of p300.
The transcriptional coactivators CREB-binding protein 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 CREB-binding protein/p300 function, modulating their transcriptional activity. In this study, we report that the viral protein A238L interacts with the amino-terminal region of p300, inhibiting the acetylation and transcriptional activation of NF-ATc2, NF-kappaB, 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 conducted through blocking protein kinase C (PKC)-p300 interaction and further acetylation in the amino-terminal transactivation domain of the coactivator, and that Ser(384), within the CH1 domain, is essential for the full transcriptional activation of the coactivator. Moreover, we show that overexpression of an active form of PKC-theta reverts the A238L-mediated inhibition of the transcriptional activity of p300, showing, for the first time, a PKC-theta-mediated up-regulation of the coactivator. These findings provide new strategies to develop therapies potentially useful in the control of disorders related to p300 deregulation.
Granja
Aitor G
AG
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Perkins
Neil D
ND
Revilla
Yolanda
Y
D000358:African Swine Fever Virus / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D000074121:Protein Kinase C-theta; D017434:Protein Structure, Tertiary / Q000235:genetics; D015533:Transcriptional Activation / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
C113585:A238L protein, African swine fever virus; D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D010446:Peptide Fragments; D014764:Viral Proteins; D050880:p300-CBP Transcription Factors; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D048031:JNK Mitogen-Activated Protein Kinases