Acetylation of adenovirus E1A regulates binding of the transcriptional corepressor CtBP

Adenovirus E1A mediates its effects on cellular transformation and transcri ption by interacting with critical cellular proteins involved in cell growt h and differentiation. The amino terminus of E1A binds to CBP/p300 and asso ciated histone acetyltransferases such as P/CAF. The carboxyl terminus bind s to the carboxyl-terminal binding protein (CtBP), which associates with hi stone deacetylases. We show that 12S E1A can be acetylated by p300 and P/CA F and map one of the acetylation sites to Lys-239. This Lys residue is adja cent to the consensus CtBP binding motif, PXDLS. Mutation of Lys-239 to Gin or Ala blocks CtBP binding in vitro and disrupts the E1A-CtBP interaction in vivo. Peptide competition assays demonstrated that the interaction of E1 A with CtBP is also blocked by Lys-239 acetylation. Supporting a functional role for Lys-239 in CtBP binding, mutation of this residue to Ala decrease s the ability of EIA to block cAMP-regulated enhancer (CRE)-binding protein (CREB)-stimulated gene expression. Finally. we demonstrate that Lys-239 is acetylated in cells by using an antibody directed against an acetyl-Lys-23 9 E1A peptide. CtBP interacts with a wide variety of other transcriptional repressors through the PXDLS motif, and, in many instances, this motif is f ollowed by a Lys residue. We suggest that acetylation of this residue by hi stone acetyltransferases, and the consequent disruption of repressor comple xes, might be a general mechanism for gene activation.