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A SUMO‐Acetyl Switch in PXR Biology
Author(s) -
Cui Wenqi,
Sun Mengxi,
Shen Xunan,
Staudinger Jeff
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1189.3
Subject(s) - pregnane x receptor , acetylation , sumo protein , hdac3 , histone deacetylase , acetyltransferase , corepressor , nuclear receptor , biology , trichostatin a , microbiology and biotechnology , chromatin immunoprecipitation , chemistry , histone , biochemistry , promoter , transcription factor , gene expression , gene , ubiquitin
Pregnane x Receptor (PXR, NR1I2) was initially described as a master‐regulator of drug‐inducible xenobiotic detoxification pathways in the enterohepatic system. However, there is increasing recognition that PXR activation has a multiplicity of ‘non‐canonical’ roles including anti‐inflammatory effects, alterations in glucose and lipid homeostasis, development of cancer therapy resistance, and in driving tumor progression. There is a clear recognition that alterations in post‐translational modifications (PTMs) of PXR play a pivotal role in regulating its biological function. Precisely how these PTMs influence each other is a current area of interest in our laboratory. We have investigated the interaction of two distinct PTMs at the level of PXR, namely, SUMOylation and acetylation. We detect acetylation of PXR in mouse hepatocytes using an immunoprecipitation approach. The enzyme that modulates PXR de‐acetylation is likely HDAC3 in a complex with a well‐known co‐repressor protein‐SMRT. PXR and HDAC3 co‐localize in mouse hepatocytes, and the acetylation alters the sub‐cellular localization of PXR. Treatment of hepatocytes with the class I histone deacetylase (HDAC) inhibitor trichostatin A (TSA) produces synergistic transactivation of a PXR‐reporter gene when combined with rifampicin, a prototypical PXR agonist. Enzymatic de‐acetylation with HDAC3/SMRT inhibits SUMO‐modification of PXR, while pharmacological promotion of acetylation with TSA promotes high levels of SUMO‐modification of PXR. Treatment with TSA produces increased acetylation of PXR in hepatocytes. The acetylation and SUMOylation of PXR also differentially modulated its ability to associate with the canonical co‐repressor proteins HDAC3/SMRT. We show that SUMOylated PXR has an intrinsic repressive function that is mediated by a currently unknown mechanism. Taken together, our data support a model in which a SUMO‐acetyl ‘switch’ occurs at the level of PXR, such that acetylation is prerequisite for SUMO‐modification of PXR to promote active repression of target gene expression. Support or Funding Information National Institute of Digestive Diabetic and Kidney Diseases (R01DK090558) National Institute of Health National Center for Research Resources COBRE (P20 GM103549) University of Kansas J.R. & Inez Jay Fund