Lysine acetyltransferases cyclic adenosine monophosphate response element‐binding binding protein and acetyltransferase p300 attenuate transcriptional activity of the mineralocorticoid receptor through its acetylation

Abstract

Acetylation of the mineralocorticoid receptor (MR) by inhibition of lysine deacetylases attenuates MR's transcriptional activity. However, the specific lysine acetyltransferases that are responsible for acetylation of the MR remain unknown. We hypothesized that the acetyltransferases cyclic adenosine monophosphate response element-binding binding protein (CBP) and acetyltransferase p300 (p300) attenuate transcriptional activity of the MR through its acetylation. Expression of MR target genes was measured by quantitative real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes was analysed by chromatin immunoprecipitation. Acetylation of the MR was determined by western blot with an anti-acetyl-lysine antibody after immunoprecipitation with an anti-MR antibody. In human embryonic kidney (HEK) 293 cells, overexpression of CBP or p300, but not p300/CBP-associated factor, increased MR acetylation and decreased expression of MR target genes. The downregulation of target genes coincided with a decrease in the recruitment of MR and Pol II to specific hormone response elements. These results demonstrate that overexpression of CBP or p300 attenuates the transcriptional activity of the MR through its acetylation in HEK 293 cells. Our data provide strong evidence identifying CBP and p300 as lysine acetyltransferases responsible for the regulation of MR that may provide new therapeutic targets for the treatment of hypertension.

The effect of acetylation on the protein stability of BmApoLp‐III in the silkworm, Bombyx mori

“…Since nonhistone acetylation was first identified, increasingly more functions for acetylation have been found to act on various life processes, including DNA damage response and autophagy (Botrugno et al, 2012;Zhong et al, 2017;Yasuda et al, 2018), genomic stability (Billon et al, 2017;Fournier and Tora, 2017), transcriptional activity (Seo et al, 2015), protein degradation (Liu et al, 2013;Wei et al, 2018) and lysosomal function (Zhang et al, 2018). Previous studies have shown that acetylation could compete with ubiquitination at the same lysine residue, thus blocking the ubiquitin-mediated proteasomal degradation pathway to improve the protein stability, which is involved in cell cycle regulation (Lahusen et al, 2018), tumour suppression and progression (Wan et al, 2015;Choi et al, 2017), bacterial virulence (Sang et al, 2017) and signal transduction (Garcia-Aguilar et al, 2016;Beckwith et al, 2018;Wei et al, 2018).…”

“…ApoLp-III, as an RNA binding protein, sends out an alarm signal by binding to a specific RNA during bacterial invasion (Park et al, 2005). ApoLp-III is also involved in many insect immune responses, such as those of Heliothis virescens (Gupta et al, 2010), Hyphantria cunea (Contreras et al, 2013), Anopheles gambiae (Lourenco et al, 2009) and Tribolium castaneum Herbst (Seo et al, 2015).…”

Acetylation of nuclear receptors in health and disease: an update

“…Inhibition of class 1 HDACs promoted MR acetylation, attenuated recruitment of MR and RNA polymerase II to the promoters of target genes and reduced expression of MR target genes [100] manifesting as decreased transcriptional activity [102]. CBP or p300 increased MR acetylation, decreased recruitment of MR and Pol II to specific hormone response elements and decreased expression of MR target genes in HEK cells [102,103] without affecting sub‐cellular localization.…”

Post-Translational Modification of MR Activity

“…Surprisingly, K677 acetylation did not affect MR nuclear translocation [36], even though this residue is located in NL1. This study and subsequent work by the same group identified CREB-binding protein (CRE)/p300 as the acetylase and HDAC3 as the deacetylase responsible for modifying K677 [36,73] (Figure 2). The molecular basis for the lack of MR binding to target promoters when acetylated at residue K677, which is away from the DBD, is unknown.…”