Acetylation of RORβ by histone acetyltransferase p300 and deacetylation by SIRT1 modulates receptor stability, turnover and transcriptional activity
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Abstract
RORβ 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 RORβ. Crosslinking mass spectrometry (XL-MS) confirmed that p300 interacts with the DNA binding domain (DBD), hinge region, and ligand binding domain (LBD) of RORβ. Both p300 and SIRT1 impact the turnover rate and transcriptional activity of RORβ. p300-dependent acetylation sites were found to be constrained to the DBD and hinge region of RORβ 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 RORβ at distal sites. Uncovering regulatory mechanisms of RORβ via protein interactions and PTMs will provide strategies for development of therapeutics targeting the receptor.
Teaser
p300 and SIRT1 work in concert to coordinate posttranslational modifications of the nuclear receptor RORβ.
Graphical Abstract
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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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