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Functional studies of the deubiquitinating enzymes USP19, USP4 and UCH-L1

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dc.contributor.advisorLindsten, Kristina
dc.contributor.advisorMasucci, Maria Grazia
dc.contributor.advisorCamacho Navarro, María Marcela
dc.creatorVelasco Pinto, Kelly Marcela
dc.creator.degreeDoctor en Ciencias Biomédicas
dc.date.accessioned2014-04-28T21:12:52Z
dc.date.available2014-04-28T21:12:52Z
dc.date.created2013-12-02
dc.date.issued2013
dc.descriptionEl marcaje de proteínas con ubiquitina, conocido como ubiquitinación, cumple diferentes funciones que incluyen la regulación de varios procesos celulares, tales como: la degradación de proteínas por medio del proteosoma, la reparación del ADN, la señalización mediada por receptores de membrana, y la endocitosis, entre otras (1). Las moléculas de ubiquitina pueden ser removidas de sus sustratos gracias a la acción de un gran grupo de proteasas, llamadas enzimas deubiquitinizantes (DUBs) (2). Las DUBs son esenciales para la manutención de la homeostasis de la ubiquitina y para la regulación del estado de ubiquitinación de diferentes sustratos. El gran número y la diversidad de DUBs descritas refleja tanto su especificidad como su utilización para regular un amplio espectro de sustratos y vías celulares. Aunque muchas DUBs han sido estudiadas a profundidad, actualmente se desconocen los sustratos y las funciones biológicas de la mayoría de ellas. En este trabajo se investigaron las funciones de las DUBs: USP19, USP4 y UCH-L1. Utilizando varias técnicas de biología molecular y celular se encontró que: i) USP19 es regulada por las ubiquitin ligasas SIAH1 y SIAH2 ii) USP19 es importante para regular HIF-1α, un factor de transcripción clave en la respuesta celular a hipoxia, iii) USP4 interactúa con el proteosoma, iv) La quimera mCherry-UCH-L1 reproduce parcialmente los fenotipos que nuestro grupo ha descrito previamente al usar otros constructos de la misma enzima, y v) UCH-L1 promueve la internalización de la bacteria Yersinia pseudotuberculosis.spa
dc.description.abstractThe conjugation of ubiquitin to proteins, known as ubiquitination, has different cellular functions; they include targeting proteins for degradation by the proteasome, regulation of DNA damage repair signaling, membrane receptor signaling and endocytosis (1). The ubiquitin moieties can be de-conjugated from their substrates or other ubiquitin moieties by a large group of proteases named deubiquitinating enzymes (DUBs) (2). DUBs are essential for the maintenance of the ubiquitin homeostasis in the cell and regulation of the ubiquitination status of the different substrates. The diversity of these proteases hints on their specificity for certain targets and participation in particular cellular pathways. Although several DUBs have been thoroughly studied, at present the targets and physiological roles of most of them remain unknown. Here, we studied the functional roles of the ubiquitin specific protease 19 (USP19), USP4 and the ubiquitin C-terminal hydrolase (UCH-L1), using several cellular and molecular techniques. We found that, i) USP19 can be regulated by SIAH ubiquitin ligases, ii) USP19 is important for controlling the key regulator of response to hypoxia, HIF-1α, iii) USP4 is a proteasome-interacting DUB, iv) an mCherry-UCH-L1 chimera reproduces only partially previous phenotypes described for UCH-L1, and v) UCH-L1 promotes Yersinia pseudotuberculosis internalization.eng
dc.description.sponsorshipERACOLspa
dc.description.sponsorshipUniversidad del Rosariospa
dc.description.sponsorshipKarolinska Institutetspa
dc.format.mimetypeapplication/pdf
dc.format.tipoDocumentospa
dc.identifier.doihttps://doi.org/10.48713/10336_5113
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/5113
dc.language.isospa
dc.publisherUniversidad del Rosariospa
dc.publisher.departmentFacultad de Ciencias Naturales y Matemáticasspa
dc.publisher.programDoctorado en Ciencias Biomédicasspa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
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dc.rights.ccAtribución-NoComercial-SinDerivadas 2.5 Colombiaspa
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dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subjectUbiquitinaspa
dc.subjectEnzimas deubiquitinizantesspa
dc.subjectUSP19spa
dc.subjectUSP4spa
dc.subjectUCH-L1spa
dc.subject.ddcBiología
dc.subject.decsEnzimasspa
dc.subject.decsProteinasspa
dc.subject.decsUbiquitinaspa
dc.subject.decsEnzimas deubiquitinizantesspa
dc.subject.keywordUbiquitineng
dc.subject.keywordDeubiquitinating enzymeseng
dc.subject.keywordUCH-L1eng
dc.subject.keywordUSP19eng
dc.subject.keywordUSP4eng
dc.titleFunctional studies of the deubiquitinating enzymes USP19, USP4 and UCH-L1spa
dc.typedoctoralThesiseng
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
dc.type.spaTesis de doctoradospa
local.department.reportEscuela de Medicina y Ciencias de la Saludspa
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