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...

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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
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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Summary: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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