Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis
Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human dis...
| Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | article |
| Publication Date: | 2020 |
| Country: | España |
| Institution: | Universidad del País Vasco |
| Repository: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/49028 |
| Online Access: | http://hdl.handle.net/10810/49028 |
| Access Level: | Open access |
| Keyword: | liver fibrosis ubiquitination metabolomics proliferating cell nuclear antigen (PCNA) DNA damage response (DDR) |
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Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| title |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| spellingShingle |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis Mercado Gómez, María liver fibrosis ubiquitination metabolomics proliferating cell nuclear antigen (PCNA) DNA damage response (DDR) |
| title_short |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| title_full |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| title_fullStr |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| title_full_unstemmed |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| title_sort |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| dc.creator.none.fl_str_mv |
Mercado Gómez, María Lopitz Otsoa, Fernando Azkargorta, Mikel Serrano Maciá, Marina Lachiondo Ortega, Sofía Goikoetxea Usandizaga, Naroa Rodríguez Agudo, Rubén Fernández Ramos, David Bizkarguenaga, Maider Gutiérrez de Juan, Virginia Lectez, Benoit Aloria Escolastico, Kerman Arizmendi Bastarrika, Jesús María Simón Espinosa, Jorge Alonso, Cristina Lozano, Juan José Ávila, Matías A. Bañales Asurmendi, Jesús María Marín, José J. G. Beraza, Naiara Mato, José M. Elortza, Felix Barrio Olano, María Rosa Sutherland, James D. Mayor Martínez, Ugo Martínez Chantar, María Luz Cardoso Delgado, Teresa de Jesús |
| author |
Mercado Gómez, María |
| author_facet |
Mercado Gómez, María Lopitz Otsoa, Fernando Azkargorta, Mikel Serrano Maciá, Marina Lachiondo Ortega, Sofía Goikoetxea Usandizaga, Naroa Rodríguez Agudo, Rubén Fernández Ramos, David Bizkarguenaga, Maider Gutiérrez de Juan, Virginia Lectez, Benoit Aloria Escolastico, Kerman Arizmendi Bastarrika, Jesús María Simón Espinosa, Jorge Alonso, Cristina Lozano, Juan José Ávila, Matías A. Bañales Asurmendi, Jesús María Marín, José J. G. Beraza, Naiara Mato, José M. Elortza, Felix Barrio Olano, María Rosa Sutherland, James D. Mayor Martínez, Ugo Martínez Chantar, María Luz Cardoso Delgado, Teresa de Jesús |
| author_role |
author |
| author2 |
Lopitz Otsoa, Fernando Azkargorta, Mikel Serrano Maciá, Marina Lachiondo Ortega, Sofía Goikoetxea Usandizaga, Naroa Rodríguez Agudo, Rubén Fernández Ramos, David Bizkarguenaga, Maider Gutiérrez de Juan, Virginia Lectez, Benoit Aloria Escolastico, Kerman Arizmendi Bastarrika, Jesús María Simón Espinosa, Jorge Alonso, Cristina Lozano, Juan José Ávila, Matías A. Bañales Asurmendi, Jesús María Marín, José J. G. Beraza, Naiara Mato, José M. Elortza, Felix Barrio Olano, María Rosa Sutherland, James D. Mayor Martínez, Ugo Martínez Chantar, María Luz Cardoso Delgado, Teresa de Jesús |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
liver fibrosis ubiquitination metabolomics proliferating cell nuclear antigen (PCNA) DNA damage response (DDR) |
| topic |
liver fibrosis ubiquitination metabolomics proliferating cell nuclear antigen (PCNA) DNA damage response (DDR) |
| description |
Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis. |
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2020 |
| dc.date.none.fl_str_mv |
2020 2020 2020 2020 |
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info:eu-repo/semantics/article |
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article |
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http://hdl.handle.net/10810/49028 |
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http://hdl.handle.net/10810/49028 |
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Inglés |
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Inglés |
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info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/3.0/es/ |
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Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver FibrosisMercado Gómez, MaríaLopitz Otsoa, FernandoAzkargorta, MikelSerrano Maciá, MarinaLachiondo Ortega, SofíaGoikoetxea Usandizaga, NaroaRodríguez Agudo, RubénFernández Ramos, DavidBizkarguenaga, MaiderGutiérrez de Juan, VirginiaLectez, BenoitAloria Escolastico, KermanArizmendi Bastarrika, Jesús MaríaSimón Espinosa, JorgeAlonso, CristinaLozano, Juan JoséÁvila, Matías A.Bañales Asurmendi, Jesús MaríaMarín, José J. G.Beraza, NaiaraMato, José M.Elortza, FelixBarrio Olano, María RosaSutherland, James D.Mayor Martínez, UgoMartínez Chantar, María LuzCardoso Delgado, Teresa de Jesúsliver fibrosisubiquitinationmetabolomicsproliferating cell nuclear antigen (PCNA)DNA damage response (DDR)Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.This work was supported by grants from Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C.), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C.), Ministerio de Ciencia, Innovación y Universidades MICINN: SAF2017-87301-R, SAF2017-88041-R, RTI2018-096759-A-100 and SAF2016-76898-P integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación, cofinanciado con Fondos FEDER (to M.L.M.-C., J.M.M., T.C.D. and U.M. respectively); AECC Bizkaia (M.S.-M.); Asociación Española contra el Cáncer (T.C.D.), Fundación Científica de la Asociación Española Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M., J.M.B., M.A.A., J.J.G.M.), La Caixa Foundation Program (to M.L.M.), 2018 BBVA Foundation Grants for Scientific Research Teams (to M.L.M.-C.). This research was also funded by the CIBERehd (EHD15PI05/2016) and “Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III”, Spain (PI16/00598 and PI19/00819, co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”); Spanish Ministry of Economy, Industry and Competitiveness (SAF2016-75197-R); “Junta de Castilla y Leon” (SA063P17); AECC Scientific Foundation (2017/2020), Spain; “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain; University of Salamanca Foundation, Spain (PC-TCUE18-20_051), and Fundació Marato TV3 (Ref. 201916-31), Spain (to J.J.G.M.). The UPV/EHU Lab and the Proteomics Platform are members of Proteored, PRB3 and is supported by grant PT17/0019, of the PE I + D + i 2013-2016, funded by ISCIII and ERDF. Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644).MDPI2020202020202020info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/49028reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MCIU/SAF2017-87301-R/info:eu-repo/grantAgreement/MCIU/SAF2017-88041-R/info:eu-repo/grantAgreement/MCIU/RTI2018-096759-A-100/info:eu-repo/grantAgreement/MCIU/SAF2016-76898-P/info:eu-repo/grantAgreement/MINECO/SAF2016-75197-R/https://www.mdpi.com/1422-0067/21/23/9043/htminfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).oai:addi.ehu.eus:10810/490282026-06-18T09:23:17Z |
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15.300719 |