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2016 ; 1859
(9
): 1170-1182
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A SUMO-acetyl switch in PXR biology
#MMPMID26883953
Cui W
; Sun M
; Zhang S
; Shen X
; Galeva N
; Williams TD
; Staudinger JL
Biochim Biophys Acta
2016[Sep]; 1859
(9
): 1170-1182
PMID26883953
show ga
Post-translational modification (PTM) of nuclear receptor superfamily members
regulates various aspects of their biology to include sub-cellular localization,
the repertoire of protein-binding partners, as well as their stability and mode
of degradation. The nuclear receptor pregnane X receptor (PXR, NR1I2) is a
master-regulator of the drug-inducible gene expression in liver and intestine.
The PXR-mediated gene activation program is primarily recognized to increase drug
metabolism, drug transport, and drug efflux pathways in these tissues. The
activation of PXR also has important implications in significant human diseases
including inflammatory bowel disease and cancer. Our recent investigations reveal
that PXR is modified by multiple PTMs to include phosphorylation, SUMOylation,
and ubiquitination. Using both primary cultures of hepatocytes and cell-based
assays, we show here that PXR is modified through acetylation on lysine residues.
Further, we show that increased acetylation of PXR stimulates its increased
SUMO-modification to support active transcriptional suppression. Pharmacologic
inhibition of lysine de-acetylation using trichostatin A (TSA) alters the
sub-cellular localization of PXR in cultured hepatocytes, and also has a profound
impact upon PXR transactivation capacity. Both the acetylation and SUMOylation
status of the PXR protein is affected by its ability to associate with the lysine
de-acetylating enzyme histone de-acetylase (HDAC)3 in a complex with silencing
mediator of retinoic acid and thyroid hormone receptor (SMRT). Taken together,
our data support a model in which a SUMO-acetyl 'switch' occurs such that
acetylation of PXR likely stimulates SUMO-modification of PXR to promote the
active repression of PXR-target gene expression. This article is part of a
Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog,
edited by Dr. Wen Xie.
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