MECHANISMS FOR REGULATING SELECTIVE AUTOPHAGIA BY HERC LIGASE UBICUITIN (Q3152182): Difference between revisions
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(Created claim: summary (P836): AUTOPHAGIA AND THE UBICUITIN-PROTEASOME SYSTEM ARE THE MAIN SYSTEMS OF DEGRADATION OF INTRACELLULAR COMPONENTS. WHILE THE UBICUITIN-PROTEASOME SYSTEM ELIMINATES INDIVIDUALLY POLIUBICUITILATE PROTEINS, AUTOPHAGIA (MACROAUTOPHAGIA) SELECTIVELY ENCAPSULATES CYTOPLASMIC COMPONENTS AS PROTEIN AGGREGATES, ORGANULOS OR PATHOGENS FOR FURTHER DEGRADATION IN THE AUTOLISOSOMA. THE DEREGULATION OF THESE SYSTEMS IS RELATED TO IMPORTANT HUMAN PATHOLOGIES SUCH...) |
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MÉCANISMES DE RÉGULATION DE L’AUTOPHAGIE SÉLECTIVE PAR HERC LIGASE UBICUITIN | |||
Revision as of 16:40, 2 December 2021
Project Q3152182 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | MECHANISMS FOR REGULATING SELECTIVE AUTOPHAGIA BY HERC LIGASE UBICUITIN |
Project Q3152182 in Spain |
Statements
78,650.0 Euro
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157,300.0 Euro
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50.0 percent
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30 December 2016
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31 December 2020
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UNIVERSIDAD DE BARCELONA
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41°21'35.50"N, 2°5'59.24"E
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08101
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LA AUTOFAGIA Y EL SISTEMA UBICUITINA-PROTEASOMA SON LOS PRINCIPALES SISTEMAS DE DEGRADACION DE COMPONENTES INTRACELULARES. MIENTRAS EL SISTEMA UBICUITINA-PROTEASOMA ELIMINA PROTEINAS INDIVIDUALMENTE POLIUBICUITILADAS, LA AUTOFAGIA (MACROAUTOFAGIA) ENCAPSULA SELECTIVAMENTE COMPONENTES CITOPLASMATICOS COMO AGREGADOS PROTEICOS, ORGANULOS O PATOGENOS PARA SU DEGRADACION POSTERIOR EN EL AUTOLISOSOMA. LA DESREGULACION DE ESTOS SISTEMAS SE RELACIONA CON IMPORTANTES PATOLOGIAS HUMANAS COMO LAS ENFERMEDADES NEURODEGENERATIVAS ASOCIADAS A LA AGREGACION PROTEICA Y EL CANCER. LAS UBICUITINA LIGASAS HERC ESTAN EMERGIENDO COMO REGULADORES DE PROCESOS FISIOLOGICOS TAN IMPORTANTES COMO EL CRECIMIENTO, LA RESPUESTA INMUNE, LA REPARACION DEL ADN Y LA RESPUESTA CELULAR AL STRESS. EN HUMANOS, MUTACIONES EN LAS UBICUITINA LIGASAS HERC1 Y HERC2 SE HAN ASOCIADO CON DESCOORDINACION MOTORA, SINDROMES GRAVES DEL DESARROLLO COMO EL SINDROME DE ANGELMAN, Y CON DIFERENTES TIPOS DE CANCER. EN LOS ULTIMOS AÑOS, SE HA DEMOSTRADO UN PAPEL IMPORTANTE DE LAS UBICUITINA LIGASAS HERC EN AUTOFAGIA. INICIALMENTE, DEMOSTRAMOS EN RATONES MUTANTES DE HERC1 CAUSANTES DEL FENOTIPO ATAXICO DENOMINADO TAMBALEANTE, UNA PERDIDA DE CELULAS DE PURKINJE ASOCIADA A UN INCREMENTO DE LA AUTOFAGIA. POSTERIORMENTE, SE DEMOSTRO QUE HERC2 FORMA UN COMPLEJO CON NEURL4 Y LA PROTEINA QUINASA ASOCIADA AL PARKINSON DENOMINADA LRRK2. LRRK2 REGULA MITOFAGIA Y SU DESREGULACION PRODUCE LA DISFUNCION MITOCONDRIAL. HERC2 REGULA TAMBIEN FERRITINOFAGIA VIA EL RECEPTOR DE FERRITINA NCOA4. HERC2 INTERACCIONA CON NCOA4 REGULANDO SU UBICUITILACION Y DEGRADACION PROTEOSOMAL DEPENDIENDO DE LOS NIVELES DE HIERRO INTRACELULAR. DE ESTA MANERA HERC2 REGULA LA DISPONIBILIDAD DE HIERRO INTRACELULAR Y AFECTA ENTRE OTROS PROCESOS A LA ERITROPOYESIS. MAS RECIENTEMENTE, HEMOS OBSERVADO UNA INTERACCION DE LAS PROTEINAS HERC1 Y HERC2 CON EL RECEPTOR DE LA AUTOFAGIA SELECTIVA P62/SQSTM1 ASI COMO UNA REGULACION DE LA AUTOFAGIA Y DE LA PROLIFERACION CELULAR DEPENDIENTE DE LA EXPRESION DE LAS PROTEINAS HERC. A PESAR DE TODA ESTA RELEVANCIA FISIOPATOLOGICA, LOS MECANISMOS DE ACTUACION DE LAS PROTEINAS HERC EN AUTOFAGIA SON MUY POCO CONOCIDOS. CON ESTE PROYECTO PRETENDEMOS CONOCER LOS MECANISMOS QUE REGULAN LA AUTOFAGIA SELECTIVA DEPENDIENTE DE LAS UBICUITINA LIGASAS HERC. ASI QUE ANALIZAREMOS LA RELEVANCIA FUNCIONAL DE LA INTERACION DE LAS PROTEINAS HERC CON LOS COMPONENTES DE LA RUTA AUTOFAGICA. ESTUDIAREMOS COMO LAS PROTEINAS HERC REGULAN LAS DIFERENTES ESTAPAS DE PROCESO AUTOFAGICO. Y, POR ULTIMO, ANALIZAREMOS COMO LA AUTOFAGIA Y LAS PROTEINAS HERC REGULAN LA PROLIFERACION CELULAR. ES NECESARIO CONOCER LOS MECANISMOS QUE REGULAN LA AUTOFAGIA PARA ENTENDER COMO SU DESREGULACION SE ASOCIA A ENFERMEDADES TAN DIFERENTES COMO EL PARKINSON O EL CANCER. ESTE CONOCIMIENTO SERVIRA PARA ACONSEJAR CONDUCTAS PREVENTIVAS Y DISEÑAR ESTRATEGIAS TERAPEUTICAS MAS EFICACES. LA REALIZACION DE ESTE PROYECTO PERMITIRA AVANZAR EN EL CONOCIMIENTO DEL PROCESO AUTOFAGICO Y SU REGULACION POR UBICUITINAS LIGASAS, Y CONTRIBUIR A EXPLICAR SUS IMPLICACIONES PATOLOGICAS. POR TODAS ESTAS RAZONES ES DE ESPERAR QUE LOS RESULTADOS DE ESTE PROYECTO TENGAN UN GRAN INTERES Y REPERCUSION EN EL AREA DE LA FISIOLOGIA Y LA BIOMEDICINA. (Spanish)
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AUTOPHAGIA AND THE UBICUITIN-PROTEASOME SYSTEM ARE THE MAIN SYSTEMS OF DEGRADATION OF INTRACELLULAR COMPONENTS. WHILE THE UBICUITIN-PROTEASOME SYSTEM ELIMINATES INDIVIDUALLY POLIUBICUITILATE PROTEINS, AUTOPHAGIA (MACROAUTOPHAGIA) SELECTIVELY ENCAPSULATES CYTOPLASMIC COMPONENTS AS PROTEIN AGGREGATES, ORGANULOS OR PATHOGENS FOR FURTHER DEGRADATION IN THE AUTOLISOSOMA. THE DEREGULATION OF THESE SYSTEMS IS RELATED TO IMPORTANT HUMAN PATHOLOGIES SUCH AS NEURODEGENERATIVE DISEASES ASSOCIATED WITH PROTEIN AGGREGATION AND CANCER. HERC LIGASE UBICUITIN ARE EMERGING AS REGULATORS OF PHYSIOLOGICAL PROCESSES AS IMPORTANT AS GROWTH, IMMUNE RESPONSE, DNA REPAIR AND CELLULAR RESPONSE TO STRESS. IN HUMANS, MUTATIONS IN UBICUITIN LIGASE HERC1 AND HERC2 HAVE BEEN ASSOCIATED WITH MOTOR DECOORDINATION, SEVERE DEVELOPMENTAL SYNDROMES SUCH AS ANGELMAN SYNDROME, AND WITH DIFFERENT TYPES OF CANCER. OVER THE LAST FEW YEARS, AN IMPORTANT ROLE OF HERC LIGASE UBICUITIN HAS BEEN SHOWN IN AUTOPHAGIA. INITIALLY, WE DEMONSTRATED IN MUTANT HERC1 MICE CAUSING THE ATAXICO PHENOTYPE CALLED TAMBALEANT, A LOSS OF PURKINJE CELLS ASSOCIATED WITH AN INCREASE IN AUTOPHAGIA. SUBSEQUENTLY, HERC2 IS SHOWN TO FORM A COMPLEX WITH NEURL4 AND THE PARKINSON-ASSOCIATED PROTEIN KINASE CALLED LRRK2. LRRK2 REGULATES MITOPHAGIA AND ITS DEREGULATION PRODUCES MITOCHONDRIAL DYSFUNCTION. HERC2 ALSO REGULATES FERRITINOFAGIA VIA THE NCOA4 FERRITIN RECEIVER. HERC2 INTERACTS WITH NCOA4 REGULATING ITS UBICUITILATION AND PROTEOSOMAL DEGRADATION DEPENDING ON INTRACELLULAR IRON LEVELS. IN THIS WAY HERC2 REGULATES THE AVAILABILITY OF INTRACELLULAR IRON AND AFFECTS AMONG OTHER PROCESSES ERYTHROPOIESIS. MORE RECENTLY, WE HAVE OBSERVED AN INTERACTION OF THE HERC1 AND HERC2 PROTEINS WITH THE SELECTIVE AUTOPHAGIA RECEPTOR P62/SQSTM1 AS WELL AS A REGULATION OF AUTOPHAGIA AND CELL PROLIFERATION DEPENDENT ON THE EXPRESSION OF HERC PROTEINS. DESPITE ALL THIS RELEVANCE PHYSIOPATOLOGICAL, THE MECHANISMS OF ACTION OF HERC PROTEINS IN AUTOPHAGIA ARE VERY LITTLE KNOWN. WITH THIS PROJECT WE INTEND TO KNOW THE MECHANISMS THAT REGULATE SELECTIVE AUTOPHAGIA DEPENDENT ON THE HERC LIGASE UBICUITIN. SO WE'LL ANALYSE THE FUNCTIONAL RELEVANCE OF THE INTERACTION OF HERC PROTEINS WITH THE COMPONENTS OF THE AUTOFAGICA ROUTE. WE WILL STUDY HOW HERC PROTEINS REGULATE THE DIFFERENT AUTOFAGICO PROCESS STAPLES. AND FINALLY, WE'LL ANALYSE HOW AUTOPHAGIA AND HERC PROTEINS REGULATE CELL PROLIFERATION. IT IS NECESSARY TO KNOW THE MECHANISMS THAT REGULATE AUTOPHAGIA TO UNDERSTAND HOW ITS DEREGULATION IS ASSOCIATED WITH DISEASES AS DIFFERENT AS PARKINSON OR CANCER. THIS KNOWLEDGE WILL SERVE TO ADVISE PREVENTIVE BEHAVIORS AND DESIGN MORE EFFECTIVE THERAPEUTIC STRATEGIES. THE REALISATION OF THIS PROJECT WILL ALLOW PROGRESS IN THE KNOWLEDGE OF THE AUTOFAGICO PROCESS AND ITS REGULATION BY LIGASE UBICUITINS, AND CONTRIBUTE TO EXPLAIN ITS PATHOLOGICAL IMPLICATIONS. FOR ALL THESE REASONS IT IS TO BE HOPED THAT THE RESULTS OF THIS PROJECT WILL HAVE A GREAT INTEREST AND IMPACT ON THE AREA OF PHYSIOLOGY AND BIOMEDICINE. (English)
12 October 2021
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Hospitalet de Llobregat, L'
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Identifiers
BFU2016-80295-R
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