African swine fever virus blocks the host cell antiviral inflammatory response through a direct inhibition of PKC-theta-mediated p300 transactivation.
During a viral infection, reprogramming of the host cell gene expression pattern is required to establish an adequate antiviral response. The transcriptional coactivators p300 and CREB binding protein (CBP) play a central role in this regulation by promoting the assembly of transcription enhancer complexes to specific promoters of immune and proinflammatory genes. Here we show that the protein A238L encoded by African swine fever virus counteracts the host cell inflammatory response through the control of p300 transactivation during the viral infection. We demonstrate that A238L inhibits the expression of the inflammatory regulators cyclooxygenase-2 (COX-2) and tumor necrosis factor alpha (TNF-alpha) by preventing the recruitment of p300 to the enhanceosomes formed on their promoters. Furthermore, we report that A238L inhibits p300 activity during the viral infection and that its amino-terminal transactivation domain is essential in the A238L-mediated inhibition of the inflammatory response. Importantly, we found that the residue serine 384 of p300 is required for the viral protein to accomplish its inhibitory function and that ectopically expressed PKC-theta completely reverts this inhibition, thus indicating that this signaling pathway is disrupted by A238L during the viral infection. Furthermore, we show here that A238L does not affect PKC-theta enzymatic activity, but the molecular mechanism of this viral inhibition relies on the lack of interaction between PKC-theta and p300. These findings shed new light on how viruses alter the host cell antiviral gene expression pattern through the blockade of the p300 activity, which represents a new and sophisticated viral mechanism to evade the inflammatory and immune defense responses.
Granja
Aitor G
AG
Centro de Biología Molecular Severo Ochoa, CSIC, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Sánchez
Elena G
EG
Sabina
Prado
P
Fresno
Manuel
M
Revilla
Yolanda
Y
D000358:African Swine Fever Virus / Q000276:immunology* / Q000502:physiology*; D000818:Animals; D002522:Chlorocebus aethiops; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism*
C113585:A238L protein, African swine fever virus; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D051546:Cyclooxygenase 2; D050881:E1A-Associated p300 Protein; D011493:Protein Kinase C