SIRT1 is a transcriptional enhancer of the glucocorticoid receptor acting independently to its deacetylase activity

Abstract

Glucocorticoids have strong effects on diverse human activities through the glucocorticoid receptor (GR). Sirtuin 1 (SIRT1) is a NAD-dependent histone deacetylase and promotes longevity by influencing intermediary metabolism and other regulatory activities including mitochondrial function. In this study, we examined the effects of SIRT1 on GR-mediated transcriptional activity. We found that SIRT1 enhanced GR-induced transcriptional activity on endogenous and exogenous glucocorticoid-responsive genes, whereas knockdown of SIRT1 attenuated it. This effect of SIRT1 was independent to its deacetylase activity, as the SIRT1 mutant defective in this activity (H363Y) enhanced GR transcriptional activity, and the compounds inhibiting or activating the SIRT1 deacetylase activity did not influence it. RNA-seq analysis revealed that SIRT1 knockdown influenced ∼30% of the glucocorticoid-responsive transcriptome for most of which it acted as an enhancer for positive/negative effects of this hormone. SIRT1 physically interacted with GR, and was attracted to GR-bound glucocorticoid response elements in a glucocorticoid-dependent fashion. SIRT1 cooperatively activated GR transcriptional activity with the PPARγ coactivator-1α also in its deacetylase activity-independent fashion. Thus, SIRT1 is a novel transcriptional enhancer of GR-induced transcriptional activity possibly by functioning as a scaffold for the transcriptional complex formed on GR.

Catalytic-independent neuroprotection by SIRT1 is mediated through interaction with HDAC1

“…A similar conclusion was reached by Singh et al who described that a catalytically-dead point-mutant form, of SIRT1, H363Y, was protective in a cell culture model of Parkinson’s disease [11]. Other studies using other non-neuronal cell types have described that some other properties and functions of SIRT1 are also independent of its catalytic activity [23–25].…”

“…A recent study by Singh et al also described that SIRT1 could protect SH-SY5Y neuroblastoma cells from rotenone toxicity and reduced α-synuclein aggregation through a catalytically-independent mechanism [11]. Furthermore, other functions of SIRT1 in non-neuronal cells can also be mediated independent of its catalytic activity [23–25]. These studies suggest that SIRT1 can function both through its enzymatic activity and through other mechanisms independent of it.…”

Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

“…In addition, GR facilitates recruitment of widely expressed coactivators including histone acetyl transferases CBP, P300, GRIP1, PCAF and SRC-2 and components of the Mediator complex such as MED1 and MED14 ( 56 , 66 , 73 , 89 , 90 ). Moreover, other important GR coactivators have been identified in the liver, including CRTC2 ( 91 ), SIRT1, PGC-1α ( 92 ), ASCOM complex ( 93 ) and SETDB2 ( 94 ). On the other hand, GR has been found to interact with corepressors including SMRT ( 95 ), HDAC1 ( 96 ), CtBP ( 97 ), SMAD6-HDAC3 ( 98 ), CRY1 ( 99 ) and recently TAZ ( 100 ), although these interactions are not necessarily associated with transcriptional repression.…”

The Versatility of Sirtuin-1 in Endocrinology and Immunology

“…At a molecular level, SIRT1 can physically interact with GR and glucocorticoid inducible proteins. SIRT1 further colocalizes with GR in the nucleus upon dexamethasone treatment and regulates GR transcriptional activity by cooperating with PGC1α in a deacetylase independent manner as shown in three different human cancer (cervical, colon, hepatic) cell lines (Suzuki et al, 2018). This suggests an important role of SIRT1 and GR interplay in various human diseases.…”