Authors
Timothy R O'Leary, Denis Shutin, Nadeska I Montalvan, Nereida M Abad-Yang, Vuong Dang, Dean P Edwards, Patrick R Griffin, Mi Ra Chang
Published in
bioRxiv : the preprint server for biology. Jun 29, 2026. Epub Jun 29, 2026.
Abstract
Retinoic acid receptor-related orphan receptor beta (RORβ) 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 RORβ 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 RORβ stability and transcriptional activity. p300-mediated acetylation increases RORβ 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 RORβ for proteasomal degradation and reducing transcriptional output, providing a mechanistic framework for targeting RORβ in neurological and retinal disorders, and bone homeostasis.
p300 acetylates RORβ at eight lysines; SIRT1 reverses this via catalytic activityK176 acetylation primes UBC9/PIAS1-mediated SUMOylation at nearby K179SUMOylated RORβ undergoes proteasomal degradation leading to reduced RORβ-mediated transcriptional outputp300 displaces ubiquitin E3 ligases from RORβ; SIRT1 activation reduces PIAS1 association.
O'Leary et al. define a post-translational circuit in which p300 acetylates K176 within the RORβ hinge domain, priming SUMOylation at nearby K179 preferentially by UBC9/PIAS1. SUMOylated RORβ 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 RORβ.Graphical Abstract.
PMID:
42427505
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.
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