PLDLS-dependent interaction of E1A with CtBP: regulation of CtBP nuclear localization and transcriptional functions.
C-terminal binding proteins (CtBPs) are cellular corepressors that are targeted by adenovirus E1A. A conserved motif of E1A (PLDLS) interacts with an N-terminal hydrophobic cleft of CtBPs. Many cellular cofactors also interact with CtBPs through PLDLS-like motifs. E1A interaction with CtBP2 changed the composition of the CtBP2 protein complex and enhanced CtBP2 acetylation. We have identified a mutant of CtBP2 (M48A) that fails to interact with cellular cofactors while interacting normally with E1A. Other cleft mutations in CtBP2 affected interaction of both cellular cofactors and E1A. The M48A mutant did not repress the cellular E-cadherin promoter but inhibited transactivation mediated by the E1A N-terminal region through interaction with the E1A PLDLS motif. In vitro, E1A enhanced CtBP2 acetylation by p300 via a mechanism involving dissociation of acetylated CtBP2 from p300. E1A enhanced nuclear localization of CtBP1 as well as a cytoplasmically localized acetylation-deficient mutant of CtBP2 (3KR-CtBP2) through PLDLS-dependent interaction. Chromatin immunoprecipitation assays revealed presence of CtBP2 on E-cadherin and c-fos promoters. While E1A did not significantly alter targeting of CtBP2 to the E-cadherin and c-fos promoters, it dramatically enhanced promoter targeting of 3KR-CtBP2. Our results raise a possibility that E1A may gain access to cellular promoters through PLDLS-dependent interaction with CtBPs.
Zhao
L-J
LJ
Institute for Molecular Virology, Saint Louis University Health Sciences Center, St Louis, MO 63110, USA.
Subramanian
T
T
Vijayalingam
S
S
Chinnadurai
G
G
D000107:Acetylation; D017500:Adenovirus E1A Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000429:Alcohol Oxidoreductases; D019943:Amino Acid Substitution; D000818:Animals; D056970:Co-Repressor Proteins; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000378:metabolism; D014158:Transcription, Genetic
D017500:Adenovirus E1A Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; C111341:Ctbp2 protein, mouse