Cargando…
Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics
The conjugative metabolism mediated by UDP-glucuronosyltransferase enzymes (UGTs) significantly influences the bioavailability and biological responses of endogenous molecule substrates and xenobiotics including drugs. UGTs participate in the regulation of cellular homeostasis by limiting stress ind...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290407/ https://www.ncbi.nlm.nih.gov/pubmed/28217095 http://dx.doi.org/10.3389/fphar.2017.00023 |
_version_ | 1782504631043096576 |
---|---|
author | Rouleau, Michèle Audet-Delage, Yannick Desjardins, Sylvie Rouleau, Mélanie Girard-Bock, Camille Guillemette, Chantal |
author_facet | Rouleau, Michèle Audet-Delage, Yannick Desjardins, Sylvie Rouleau, Mélanie Girard-Bock, Camille Guillemette, Chantal |
author_sort | Rouleau, Michèle |
collection | PubMed |
description | The conjugative metabolism mediated by UDP-glucuronosyltransferase enzymes (UGTs) significantly influences the bioavailability and biological responses of endogenous molecule substrates and xenobiotics including drugs. UGTs participate in the regulation of cellular homeostasis by limiting stress induced by toxic molecules, and by controlling hormonal signaling networks. Glucuronidation is highly regulated at genomic, transcriptional, post-transcriptional and post-translational levels. However, the UGT protein interaction network, which is likely to influence glucuronidation, has received little attention. We investigated the endogenous protein interactome of human UGT1A enzymes in main drug metabolizing non-malignant tissues where UGT expression is most prevalent, using an unbiased proteomics approach. Mass spectrometry analysis of affinity-purified UGT1A enzymes and associated protein complexes in liver, kidney and intestine tissues revealed an intricate interactome linking UGT1A enzymes to multiple metabolic pathways. Several proteins of pharmacological importance such as transferases (including UGT2 enzymes), transporters and dehydrogenases were identified, upholding a potential coordinated cellular response to small lipophilic molecules and drugs. Furthermore, a significant cluster of functionally related enzymes involved in fatty acid β-oxidation, as well as in the glycolysis and glycogenolysis pathways were enriched in UGT1A enzymes complexes. Several partnerships were confirmed by co-immunoprecipitations and co-localization by confocal microscopy. An enhanced accumulation of lipid droplets in a kidney cell model overexpressing the UGT1A9 enzyme supported the presence of a functional interplay. Our work provides unprecedented evidence for a functional interaction between glucuronidation and bioenergetic metabolism. |
format | Online Article Text |
id | pubmed-5290407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-52904072017-02-17 Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics Rouleau, Michèle Audet-Delage, Yannick Desjardins, Sylvie Rouleau, Mélanie Girard-Bock, Camille Guillemette, Chantal Front Pharmacol Pharmacology The conjugative metabolism mediated by UDP-glucuronosyltransferase enzymes (UGTs) significantly influences the bioavailability and biological responses of endogenous molecule substrates and xenobiotics including drugs. UGTs participate in the regulation of cellular homeostasis by limiting stress induced by toxic molecules, and by controlling hormonal signaling networks. Glucuronidation is highly regulated at genomic, transcriptional, post-transcriptional and post-translational levels. However, the UGT protein interaction network, which is likely to influence glucuronidation, has received little attention. We investigated the endogenous protein interactome of human UGT1A enzymes in main drug metabolizing non-malignant tissues where UGT expression is most prevalent, using an unbiased proteomics approach. Mass spectrometry analysis of affinity-purified UGT1A enzymes and associated protein complexes in liver, kidney and intestine tissues revealed an intricate interactome linking UGT1A enzymes to multiple metabolic pathways. Several proteins of pharmacological importance such as transferases (including UGT2 enzymes), transporters and dehydrogenases were identified, upholding a potential coordinated cellular response to small lipophilic molecules and drugs. Furthermore, a significant cluster of functionally related enzymes involved in fatty acid β-oxidation, as well as in the glycolysis and glycogenolysis pathways were enriched in UGT1A enzymes complexes. Several partnerships were confirmed by co-immunoprecipitations and co-localization by confocal microscopy. An enhanced accumulation of lipid droplets in a kidney cell model overexpressing the UGT1A9 enzyme supported the presence of a functional interplay. Our work provides unprecedented evidence for a functional interaction between glucuronidation and bioenergetic metabolism. Frontiers Media S.A. 2017-02-03 /pmc/articles/PMC5290407/ /pubmed/28217095 http://dx.doi.org/10.3389/fphar.2017.00023 Text en Copyright © 2017 Rouleau, Audet-Delage, Desjardins, Rouleau, Girard-Bock and Guillemette. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Rouleau, Michèle Audet-Delage, Yannick Desjardins, Sylvie Rouleau, Mélanie Girard-Bock, Camille Guillemette, Chantal Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics |
title | Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics |
title_full | Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics |
title_fullStr | Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics |
title_full_unstemmed | Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics |
title_short | Endogenous Protein Interactome of Human UDP-Glucuronosyltransferases Exposed by Untargeted Proteomics |
title_sort | endogenous protein interactome of human udp-glucuronosyltransferases exposed by untargeted proteomics |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290407/ https://www.ncbi.nlm.nih.gov/pubmed/28217095 http://dx.doi.org/10.3389/fphar.2017.00023 |
work_keys_str_mv | AT rouleaumichele endogenousproteininteractomeofhumanudpglucuronosyltransferasesexposedbyuntargetedproteomics AT audetdelageyannick endogenousproteininteractomeofhumanudpglucuronosyltransferasesexposedbyuntargetedproteomics AT desjardinssylvie endogenousproteininteractomeofhumanudpglucuronosyltransferasesexposedbyuntargetedproteomics AT rouleaumelanie endogenousproteininteractomeofhumanudpglucuronosyltransferasesexposedbyuntargetedproteomics AT girardbockcamille endogenousproteininteractomeofhumanudpglucuronosyltransferasesexposedbyuntargetedproteomics AT guillemettechantal endogenousproteininteractomeofhumanudpglucuronosyltransferasesexposedbyuntargetedproteomics |