Acetylation of RORβ by histone acetyltransferase p300 and deacetylation by SIRT1 modulates receptor stability, turnover and transcriptional activity.

ROR{beta} is an understudied nuclear receptor recently implicated in numerous pathologies. Using immunoprecipitation mass spectrometry, the transcription factor coregulatory protein and histone acetyltransferase p300 (EP300) was identified as a direct interacting protein of ROR{beta}. Crosslinking mass spectrometry (XL-MS) confirmed that p300 interacts with the DNA binding domain (DBD), hinge region, and ligand binding domain (LBD) of ROR{beta}. Both p300 and SIRT1 impact the turnover rate and transcriptional activity of ROR{beta}. p300-dependent acetylation sites were found to be constrained to the DBD and hinge region of ROR{beta} and were deacetylated by SIRT1. Sites that were ubiquitinated in the presence of p300 and SIRT1 were also discovered, with some sites sensitive to proteasome inhibitor. A constitutively acetylated mimic at K176 in the hinge prevented ubiquitination of ROR{beta} at distal sites. Uncovering regulatory mechanisms of ROR{beta} via protein interactions and PTMs will provide strategies for development of therapeutics targeting the receptor. Teaserp300 and SIRT1 work in concert to coordinate posttranslational modifications of the nuclear receptor ROR{beta}. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/621067v2_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@1c95ed8org.highwire.dtl.DTLVardef@171f144org.highwire.dtl.DTLVardef@196d643org.highwire.dtl.DTLVardef@1ccd3c7_HPS_FORMAT_FIGEXP M_FIG C_FIG