Acetylation-Primed SUMOylation Drives RORβ Turnover via a p300-SIRT1 Regulatory Axis

Retinoic acid receptor-related orphan receptor beta (ROR{beta}) is a transcription factor expressed in the central nervous system, retina, and bone that regulates circadian rhythms, retinal neurogenesis, and inflammatory signaling. Despite these critical functions, the mechanisms governing ROR{beta} stability remain poorly understood. Here, we identify a post-translational regulatory axis in which the lysine acetyltransferase p300 and the NAD-dependent deacetylase SIRT1 control ROR{beta} stability and transcriptional activity. p300-mediated acetylation increases ROR{beta} abundance, while SIRT1 modulates turnover through both catalytic and non-catalytic scaffolding mechanisms. K176 acetylation in the hinge primes UBC9/PIAS1-mediated SUMOylation at nearby K179, marking ROR{beta} for proteasomal degradation and reducing transcriptional output, providing a mechanistic framework for targeting ROR{beta} in neurological and retinal disorders, and bone homeostasis. HighlightsO_LIp300 acetylates ROR{beta} at eight lysines; SIRT1 reverses this via catalytic activity C_LIO_LIK176 acetylation primes UBC9/PIAS1-mediated SUMOylation at nearby K179 C_LIO_LISUMOylated ROR{beta} undergoes proteasomal degradation leading to reduced ROR{beta}-mediated transcriptional output C_LIO_LIp300 displaces ubiquitin E3 ligases from ROR{beta}; SIRT1 activation reduces PIAS1 association C_LI In BriefOLeary et al. define a post-translational circuit in which p300 acetylates K176 within the ROR{beta} hinge domain, priming SUMOylation at nearby K179 preferentially by UBC9/PIAS1. SUMOylated ROR{beta} is targeted for proteasomal degradation with diminished transcriptional activity, while SIRT1 deacetylase activity antagonizes this pathway via both catalytic activity and protein-protein interactions to stabilize active ROR{beta}. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/621067v3_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@16f18fforg.highwire.dtl.DTLVardef@d2208corg.highwire.dtl.DTLVardef@156d829org.highwire.dtl.DTLVardef@898e48_HPS_FORMAT_FIGEXP M_FIG C_FIG