{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:56:43Z","timestamp":1785412603328,"version":"3.56.0"},"posted":{"date-parts":[[2024,10,30]]},"group-title":"Biochemistry","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["DK133587"],"award-info":[{"award-number":["DK133587"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CA263574"],"award-info":[{"award-number":["CA263574"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,29]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>Retinoic acid receptor-related orphan receptor beta (ROR\u03b2) 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\u03b2 stability remain poorly understood. Here, we identify a post-translational regulatory axis in which the lysine acetyltransferase p300 and the NAD\u207a-dependent deacetylase SIRT1 control ROR\u03b2 stability and transcriptional activity. p300-mediated acetylation increases ROR\u03b2 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\u03b2 for proteasomal degradation and reducing transcriptional output, providing a mechanistic framework for targeting ROR\u03b2 in neurological and retinal disorders, and bone homeostasis.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>p300 acetylates ROR\u03b2 at eight lysines; SIRT1 reverses this via catalytic activity<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>K176 acetylation primes UBC9\/PIAS1-mediated SUMOylation at nearby K179<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>SUMOylated ROR\u03b2 undergoes proteasomal degradation leading to reduced ROR\u03b2-mediated transcriptional output<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>p300 displaces ubiquitin E3 ligases from ROR\u03b2; SIRT1 activation reduces PIAS1 association<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>In Brief<\/jats:title>\n                  <jats:p>O\u2019Leary et al. define a post-translational circuit in which p300 acetylates K176 within the ROR\u03b2 hinge domain, priming SUMOylation at nearby K179 preferentially by UBC9\/PIAS1. SUMOylated ROR\u03b2 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\u03b2.<\/jats:p>\n                  <jats:p>Graphical Abstract<\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"621067v3_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2024.10.30.621067","type":"posted-content","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T23:55:21Z","timestamp":1730332521000},"source":"Crossref","is-referenced-by-count":0,"title":["Acetylation-Primed SUMOylation Drives ROR\u03b2 Turnover via a p300-SIRT1 Regulatory Axis"],"prefix":"10.64898","author":[{"given":"Timothy R.","family":"O\u2019Leary","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Shutin","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadeska I.","family":"Montalvan","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458"},{"name":"Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, 10550 N Torrey Pines Rd, La Jolla, CA 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