Evidence map›Paper›PMID 26063058›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2015

SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes.

Wenqi Cui, Mengxi Sun, Nadezhda Galeva, Todd D Williams, Yoshiaki Azuma, Jeff L Staudinger

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Drug metabolism and disposition: the biological fate of chemicals, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
1.5field-weighted citation impact, top 17% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed, 24 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
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  8. Article
  9. Article
  10. Article
  11. A SUMO-acetyl switch in PXR biology.Biochimica et biophysica acta · 2016
    Article
  12. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 2 institutions in 1 country.

Wenqi CuiDepartments of Pharmacology and Toxicology (W.C., J.L.S.), Mass Spectrometry Laboratory (N.G., T.D.W.), and Molecular Biosciences, University of Kansas, Lawrence, Kansas (Y.A.); and Department of Medicine, University of California, San Diego, La Jolla, California (M.S.).
Mengxi SunDepartments of Pharmacology and Toxicology (W.C., J.L.S.), Mass Spectrometry Laboratory (N.G., T.D.W.), and Molecular Biosciences, University of Kansas, Lawrence, Kansas (Y.A.); and Department of Medicine, University of California, San Diego, La Jolla, California (M.S.).
Nadezhda GalevaDepartments of Pharmacology and Toxicology (W.C., J.L.S.), Mass Spectrometry Laboratory (N.G., T.D.W.), and Molecular Biosciences, University of Kansas, Lawrence, Kansas (Y.A.); and Department of Medicine, University of California, San Diego, La Jolla, California (M.S.).
Todd D WilliamsDepartments of Pharmacology and Toxicology (W.C., J.L.S.), Mass Spectrometry Laboratory (N.G., T.D.W.), and Molecular Biosciences, University of Kansas, Lawrence, Kansas (Y.A.); and Department of Medicine, University of California, San Diego, La Jolla, California (M.S.).
Yoshiaki AzumaDepartments of Pharmacology and Toxicology (W.C., J.L.S.), Mass Spectrometry Laboratory (N.G., T.D.W.), and Molecular Biosciences, University of Kansas, Lawrence, Kansas (Y.A.); and Department of Medicine, University of California, San Diego, La Jolla, California (M.S.).
Jeff L StaudingerDepartments of Pharmacology and Toxicology (W.C., J.L.S.), Mass Spectrometry Laboratory (N.G., T.D.W.), and Molecular Biosciences, University of Kansas, Lawrence, Kansas (Y.A.); and Department of Medicine, University of California, San Diego, La Jolla, California (M.S.) stauding@ku.edu.
University of California, San Diego · USUniversity of Kansas · US

Funding

Nuclear Receptors in Liver Health and DiseaseP20GM103549 · NIGMS · UNIVERSITY OF KANSAS MEDICAL CENTER · PI JAESCHKE, HARTMUT W. · 2012 to 2015
$8.1M
Maneuvering of Macrophage Function By Escherichia coli K1R01NS073115 · NINDS · CHILDREN'S HOSPITAL OF LOS ANGELES · PI NEMANI, PRASADARAO V · 2010 to 2014
$1.6M
Inflammation, PXR Modification and Drug DispositionR01DK090558 · NIDDK · UNIVERSITY OF KANSAS LAWRENCE · PI STAUDINGER, JEFFREY L · 2011 to 2014
$1.3M
NIDDK NIH HHS R01 DK090558NIDDK NIH HHS R01DK090558NIGMS NIH HHS P20 GM103549NINDS NIH HHS R01 NS073115
6 · The paper itself

Abstract

Several nuclear receptor (NR) superfamily members are known to be the molecular target of either the small ubiquitin-related modifier (SUMO) or ubiquitin-signaling pathways. However, little is currently known regarding how these two post-translational modifications interact to control NR biology. We show that SUMO and ubiquitin circuitry coordinately modifies the pregnane X receptor (PXR, NR1I2) to play a key role in regulating PXR protein stability, transactivation capacity, and transcriptional repression. The SUMOylation and ubiquitylation of PXR is increased in a ligand- and tumor necrosis factor alpha -: dependent manner in hepatocytes. The SUMO-E3 ligase enzymes protein inhibitor of activated signal transducer and activator of transcription-1 (STAT1) STAT-1 (PIAS1) and protein inhibitor of activated STAT Y (PIASy) drive high levels of PXR SUMOylation. Expression of protein inhibitor of activated stat 1 selectively increases SUMO(3)ylation as well as PXR-mediated induction of cytochrome P450, family 3, subfamily A and the xenobiotic response. The PIASy-mediated SUMO(1)ylation imparts a transcriptionally repressive function by ameliorating interaction of PXR with coactivator protein peroxisome proliferator-activated receptor gamma coactivator-1-alpha. The SUMO modification of PXR is effectively antagonized by the SUMO protease sentrin protease (SENP) 2, whereas SENP3 and SENP6 proteases are highly active in the removal of SUMO2/3 chains. The PIASy-mediated SUMO(1)ylation of PXR inhibits ubiquitin-mediated degradation of this important liver-enriched NR by the 26S proteasome. Our data reveal a working model that delineates the interactive role that these two post-translational modifications play in reconciling PXR-mediated gene activation of the xenobiotic response versus transcriptional repression of the proinflammatory response in hepatocytes. Taken together, our data reveal that the SUMOylation and ubiquitylation of the PXR interface in a fundamental manner directs its biologic function in the liver in response to xenobiotic or inflammatory stress.

Indexed as

AnimalsHepatocytesHumansMiceMice, KnockoutPregnane X ReceptorReceptors, SteroidSignal TransductionSumoylationUbiquitinationNR1I2 protein, humanNr1i2 protein, mousePregnane X ReceptorReceptors, Steroid

Identifiers

PMID26063058
PMCPMC4538856
OpenAlexW2280968171

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.