| Title: |
Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis |
| Authors: |
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 |
| Publisher Information: |
MDPI |
| Publication Year: |
2020 |
| Collection: |
ADDI: Repositorio Institucional de la Universidad del País Vasco / Euskal Herriko Unibertsitatea (UPV/EHU - Basque Country University) |
| Subject Terms: |
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. ; 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.); ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
info: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/htm; International Journal of Molecular Sciences 21(23) : (2020) // Article ID 9043; https://hdl.handle.net/10810/49028 |
| DOI: |
10.3390/ijms21239043 |
| Availability: |
https://hdl.handle.net/10810/49028; https://doi.org/10.3390/ijms21239043 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://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/). |
| Accession Number: |
edsbas.842FE5BC |
| Database: |
BASE |