Inhibition of NAE-dependent protein hyper-NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease
dc.contributor.author | Lee-Law, Pui Y. | |
dc.contributor.author | Olaizola Rebe, Paula | |
dc.contributor.author | Caballero Camino, Francisco Javier ![]() | |
dc.contributor.author | Izquierdo Sánchez, Laura | |
dc.contributor.author | Rodrigues, Pedro M. | |
dc.contributor.author | Perugorria Montiel, María Jesús | |
dc.contributor.author | Azkargorta, Mikel | |
dc.contributor.author | Elortza, Felix | |
dc.contributor.author | Martínez Chantar, María Luz ![]() | |
dc.contributor.author | Aspichueta Celaá, Patricia | |
dc.contributor.author | Bujanda Fernández de Pierola, Luis ![]() | |
dc.contributor.author | Drenth, Joost P. H. | |
dc.contributor.author | Bañales Asurmendi, Jesús María ![]() | |
dc.date.accessioned | 2021-09-21T12:35:25Z | |
dc.date.available | 2021-09-21T12:35:25Z | |
dc.date.issued | 2021-09 | |
dc.identifier.citation | United European Gastroenterology Journal 9(7) : 848-859 (2021) | es_ES |
dc.identifier.issn | 2050-6406 | |
dc.identifier.issn | 2050-6414 | |
dc.identifier.uri | http://hdl.handle.net/10810/53122 | |
dc.description.abstract | Background Polycystic liver diseases (PLDs) are genetic inherited disorders characterized by the progressive growth of numerous intrahepatic biliary cysts, which are the main cause of morbidity. Previous studies revealed that cystic cholangiocytes are characterized by endoplasmic reticulum stress and aberrant posttranslational modification (PTM) of proteins, in particular hyper-SUMOylation, that promote PLD pathobiology. Protein NEDDylation is a newly characterized PTM that modulates a plethora of biological processes and its dysregulation is associated with the development and progression of several human diseases. However, the role of NEDDylation in PLD remains elusive. Objective To explore the role of protein NEDDylation in PLD and its potential therapeutic regulatory value. Methods Levels and functional effects of NEDDylation, including response to Pevonedistat (first-in-class selective inhibitor of the NEDDylation E1 enzyme NAE), were assessed in vitro, in vivo, and/or in patients with PLD. NEDDylated protein levels in normal and cystic human cholangiocytes were assessed by immunoprecipitation, and the proteomic profile was further analyzed by mass spectrometry. Results and Conclusion The genes involved in the NEDDylation pathway were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture, compared to controls. Elevated levels of NEDDylated proteins were further confirmed in cystic cholangiocytes in vitro, which diminished under Pevonedistat incubation. Pevonedistat promoted apoptotic cell death and reduced proliferation in cystic cholangiocytes in vitro. Comparative proteomic profiling of NEDD8-immunoprecipitated proteins between normal and cystic cholangiocytes in culture reported candidate proteins involved in cystogenesis, mostly associated with protein biogenesis and quality control. All these data indicate that cystic cholangiocytes display increased protein NEDDylation, contributing to cell survival and proliferation, ultimately supporting hepatic cystogenesis. Targeting of protein hyper-NEDDylation in cystic cholangiocytes inhibits cystogenesis in experimental models, representing a novel therapeutic opportunity in PLD. | es_ES |
dc.description.sponsorship | Spanish Carlos III Health Institute (ISCIII), Grant/Award Numbers: CON14/00129, CPII19/00008, FIS PI12/00380, FIS PI14/ 00399, FIS PI15/01132, FIS PI17/00022, FIS PI18/01075, FIS PI20/00186, Sara Borrell CD19/00254; Diputacion Foral de Gipuzkoa, Grant/Award Numbers: DFG15/010, DFG16/004; Department of Health of the Basque Country, Grant/Award Numbers: 2015111100, 2017111010, 2019111024; Euskadi RIS3, Grant/Award Numbers: 2016222001, 2017222014, 2018222029, 2019222054, 2020333010; Department of Industry of the Basque Country, Grant/Award Number: KK-2020/00008; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: RYC-2015-17755; Ministerio de Ciencia, Innovacion y Universidades, Grant/ Award Number: SAF2017-87301-R; Ayudas para apoyar grupos de investigacion del Sistema Universitario Vasco, Grant/Award Number: IT971-16; Universita Politecnica delle Marche, Grant/Award Number: PSA2017_UNIVPM; European Association for the Study of the Liver, Grant/Award Number: Sheila Sherlock Award 2017; Spanish Ministry of Science and Innovation, Grant/Award Number: BES-2014-069148; Basque Government, Grant/Award Number: PRE_2016_1_0269; Basque Foundation for Innovation and Health Research, Grant/Award Number: BIO15/CA/016/BD; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer; La Caixa Scientific Foundation, Grant/ Award Number: HR17-00601; CIBERehd; Fondo Europeo de Desarrollo Regional Document | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Sage | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/RYC-2015-17755 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/SAF2017-87301-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/BES-2014-069148 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | hepatic cystogenesis | es_ES |
dc.subject | NAE | es_ES |
dc.subject | NEDDylation | es_ES |
dc.subject | posttranslational modifications | es_ES |
dc.subject | therapy | es_ES |
dc.subject | NEDD8-activating enzyme-inhibitor | es_ES |
dc.subject | pevonedistat TAK-924/MLN4924 | es_ES |
dc.subject | phase-I | es_ES |
dc.subject | kidney | es_ES |
dc.subject | MLN4924 | es_ES |
dc.subject | cholangiocarcinoma | es_ES |
dc.subject | activation | es_ES |
dc.subject | apoptosis | es_ES |
dc.subject | pathway | es_ES |
dc.title | Inhibition of NAE-dependent protein hyper-NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology. This is an open access article under the terms of the Creative Commons Attribution NonCommercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non commercial and no modifications or adaptations are made. | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://onlinelibrary.wiley.com/doi/epdf/10.1002/ueg2.12126 | es_ES |
dc.identifier.doi | 10.1002/ueg2.12126 | |
dc.departamentoes | Fisiología | es_ES |
dc.departamentoes | Medicina | es_ES |
dc.departamentoeu | Fisiologia | es_ES |
dc.departamentoeu | Medikuntza | es_ES |
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Except where otherwise noted, this item's license is described as © 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology. This is an open access article under the terms of the Creative Commons Attribution NonCommercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non commercial and no modifications or adaptations are made.