Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP

CtBP (carboxyl-terminal binding protein) participates in regulating cellula r development and differentiation by associating with a diverse array of tr anscriptional repressors. Most of these interactions occur through a consen sus CtBP-binding motif, PXDLS, in the repressor proteins. We previously sho wed that the CtBP-binding motif in EIA is flanked by a Lys residue and sugg ested that acetylation of this residue by the p300/CBP-associated factor P/ CAF disrupts the CtBP interaction. In this study, we show that the interact ion between CtBP and the nuclear hormone receptor corepressor RIP140 is reg ulated similarly, in this case by p300/CBP itself. CtBP was shown to intera ct with RIP140 in vitro and in vivo through a sequence, PIDLSCK, in the ami no-terminal third of the RIP140 protein. Acetylation of the Lys residue in this motif, demonstrated in vivo by using an acetylated RIP140-specific ant ibody, dramatically reduced CtBP binding. Mutation of the Lys residue to Gl n resulted in a decrease in CtBP binding in vivo and a loss of transcriptio nal repression. We suggest that p300/CBP-mediated acetylation disrupts the RIP140-CtBP complex and derepresses nuclear hormone receptor-regulated gene s. Disruption of repressor-CtBP interactions by acetylation may be a genera l mode of gene activation.