Transcription regulation of nuclear receptor PXR: Role of SUMO-1 modification and NDSM in receptor function

Choudhary, Priyanka; Kotiya, Deepak; Rana, Manjul; Subbarao, Naidu; Puri, Niti; Tyagi, Rakesh K.

doi:10.1016/j.mce.2015.11.001

Cited by 18 publications

(8 citation statements)

References 56 publications

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“…However, a recent publication indicates that PXR activity is increased following SUMO-modification [15]. We have previously found that co-expression of the SUMO E3-ligase enzyme PIAS1 modestly increases drug-inducible Cyp3a11 gene expression in hepatocytes [11].…”

Section: Resultsmentioning

confidence: 99%

A SUMO-acetyl switch in PXR biology

Cui

Sun

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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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 PXR 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.

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Section: Resultsmentioning

confidence: 99%

A SUMO-acetyl switch in PXR biology

Cui

Sun

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…Another nuclear receptor that is regulated by SUMO is the Pregnane X Receptor (PXR), which coordinates programs of fatty acid, cholesterol, and lipoprotein metabolism in the liver and the intestine [77]. In HeLa cells and mouse primary hepatocytes, SUMO1 and SUMO2/3 were shown to be conjugated to the PXR protein [78,79]. These conjugations are antagonized by the activity of several SENP proteases [80].…”

Section: Nuclear Receptorsmentioning

confidence: 99%

“…These conjugations are antagonized by the activity of several SENP proteases [80]. Mechanistically, SUMO1 conjugation was suggested to enhance PXR transcriptional capacity [78] and to inhibit its degradation by the ubiquitin-proteasome system, thereby resulting in PXR activation [80]. In contrast, the conjugation of SUMO2/3 results in the ubiquitination and degradation of PXR, demonstrating that different SUMO molecules can have opposite effects on the same target.…”

Section: Nuclear Receptorsmentioning

confidence: 99%

Not So Slim Anymore—Evidence for the Role of SUMO in the Regulation of Lipid Metabolism

Sapir

2020

Biomolecules

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One of the basic building blocks of all life forms are lipids—biomolecules that dissolve in nonpolar organic solvents but not in water. Lipids have numerous structural, metabolic, and regulative functions in health and disease; thus, complex networks of enzymes coordinate the different compositions and functions of lipids with the physiology of the organism. One type of control on the activity of those enzymes is the conjugation of the Small Ubiquitin-like Modifier (SUMO) that in recent years has been identified as a critical regulator of many biological processes. In this review, I summarize the current knowledge about the role of SUMO in the regulation of lipid metabolism. In particular, I discuss (i) the role of SUMO in lipid metabolism of fungi and invertebrates; (ii) the function of SUMO as a regulator of lipid metabolism in mammals with emphasis on the two most well-characterized cases of SUMO regulation of lipid homeostasis. These include the effect of SUMO on the activity of two groups of master regulators of lipid metabolism—the Sterol Regulatory Element Binding Protein (SERBP) proteins and the family of nuclear receptors—and (iii) the role of SUMO as a regulator of lipid metabolism in arteriosclerosis, nonalcoholic fatty liver, cholestasis, and other lipid-related human diseases.

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“…SUMOYLATION is a post-translational modification process, in which a small ubiquitin-like modifier (SUMO) protein would be added to the ligand-binding domain of PXR protein[ 67 ]. A SUMO1 binding site was discovered in the ligand-binding domain of PXR[ 68 ]. It was revealed that post SUMOYLATION there is an increase in the transcriptional activity of PXR, marked by increased transcription of PXR target genes (Figure 3A ).…”

Section: Pxr and Its Role In Counteracting Inflammationmentioning

confidence: 99%

“…Also, an increase in interaction between SUMOylated PXR and NR co-repressor (NCOR1) was observed. Thus it is speculated that post-modification, PXR protein might be able to repress NF-κB indirectly by helping to keep the co-repressors (N-COR)/HDAC3 complex intact by preventing their clearance[ 68 , 69 ]. Vice versa, endotoxin stimulus such as LPS would signal the clearance of these repressor complex from the promotor region of pro-inflammatory genes and thus enabling NF-κB to transcribe the inflammatory profile genes[ 70 ].…”

Section: Pxr and Its Role In Counteracting Inflammationmentioning

confidence: 99%

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

Mohandas

Vairappan

2017

WJH

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Bacterial translocation (BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases (CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT. The importance of PXR as the mechanistic linker molecule in the gut-liver axis and its role in regulating bacterial interactions with the host in CLD has not been explored. PubMed was used to perform an extensive literature search using the keywords PXR and bacterial translocation, PXR and chronic liver disease including cirrhosis. In an adequate expression state, PXR acts as a sensor for bile acid dysregulation and bacterial derived metabolites, and in response shapes the immune profile beneficial to the host. Activation of PXR could be therapeutic in CLD as it counter-regulates endotoxin mediated inflammation and maintains the integrity of intestinal epithelium. This review mainly focuses PXR function and its regulation in BT in the context of chronic liver diseases.

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Transcription regulation of nuclear receptor PXR: Role of SUMO-1 modification and NDSM in receptor function

Cited by 18 publications

References 56 publications

A SUMO-acetyl switch in PXR biology

A SUMO-acetyl switch in PXR biology

Not So Slim Anymore—Evidence for the Role of SUMO in the Regulation of Lipid Metabolism

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

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