Acetylation-Primed SUMOylation Drives RORβ Turnover via a p300-SIRT1 Regulatory Axis
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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.
Highlights
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p300 acetylates RORβ at eight lysines; SIRT1 reverses this via catalytic activity
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K176 acetylation primes UBC9/PIAS1-mediated SUMOylation at nearby K179
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SUMOylated RORβ undergoes proteasomal degradation leading to reduced RORβ-mediated transcriptional output
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p300 displaces ubiquitin E3 ligases from RORβ; SIRT1 activation reduces PIAS1 association
In Brief
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
Article activity feed
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The deacetylation of RORβ by SIRT1 not only enhances its transcriptional activity but also increases the stability of both RORβ and p300 when in complex.
Could the increased transcriptional activity be due to enhanced stability of RORbeta? The wording suggests that these are independent outcomes.
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Acetylation of RORβ by p300 in the presence and absence of the DNA oligomer did not show a significant effect on the extent of acetylation by p300
Do you have any evidence of RORbeta binding in vivo? It would be interesting to examine RORbeta binding to endogenous RORbeta DNA binding sites to see if acetylation changes RORbeta’s propensity to bind target genes promoters.
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The acetylated RORβ was subjected to an electrophoretic mobility shift assay (EMSA) in the presence of a 40-bp DNA oligo containing a single RORE sequence.
Do you know if p300 was bound to the ROR-DNA complex (evidence of supershift with a p300 antibody)? I'm curious if p300 binding can alter RORbeta DNA binding after RORbeta is modified?
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There were 57 putative RORβ interactors with at least 5-fold increase in abundance relative to the negative control and with a p-value less than 0.05 (n=3), with 18 of these being involved in transcriptional regulation
This is a very interesting study linking the complex interplay of RORbeta posttranslational modifications to RORbeta function-congratulations! Can you provide a list of these interacting proteins? I'm curious if any known interacting proteins were immunoprecipitated, such as co-repressors and other co-activator proteins?
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