Transcriptional Corepressor SMILE Recruits SIRT1 to Inhibit Nuclear Receptor Estrogen Receptor-related Receptor gamma Transactivation

Abstract

SMILE (small heterodimer partner interacting leucine zipper protein) has been identified as a corepressor of the glucocorticoid receptor, constitutive androstane receptor, and hepatocyte nuclear factor 4 alpha. Here we show that SMILE also represses estrogen receptor-related receptor gamma (ERR gamma) transactivation. Knockdown of SMILE gene expression increases ERR gamma activity. SMILE directly interacts with ERR gamma in vitro and in vivo. Domain mapping analysis showed that SMILE binds to the AF2 domain of ERR gamma. SMILE represses ERR gamma transactivation partially through competition with coactivators PGC-1 alpha, PGC-1 beta, and GRIP1. Interestingly, the repression of SMILE on ERR gamma is released by SIRT1 inhibitors, a catalytically inactive SIRT1 mutant, and SIRT1 small interfering RNA but not by histone protein deacetylase inhibitor. In vivo glutathione S-transferase pulldown and coimmunoprecipitation assays validated that SMILE physically interacts with SIRT1. Furthermore, the ERR gamma inverse agonist GSK5182 enhances the interaction of SMILE with ERR gamma and SMILE-mediated repression. Knockdown of SMILE or SIRT1 blocks the repressive effect of GSK5182. Moreover, chromatin immunoprecipitation assays revealed that GSK5182 augments the association of SMILE and SIRT1 on the promoter of the ERR gamma target PDK4. GSK5182 and adenoviral overexpression of SMILE cooperate to repress ERR gamma-induced PDK4 gene expression, and this repression is released by overexpression of a catalytically defective SIRT1 mutant. Finally, we demonstrated that ERR gamma regulates SMILE gene expression, which in turn inhibits ERR gamma. Overall, these findings implicate SMILE as a novel corepressor of ERR gamma and recruitment of SIRT1 as a novel repressive mechanism for SMILE and ERR gamma inverse agonist.