Objetivo Vaccinia virus (VACV), the prototypic poxvirus, is a large, enveloped, DNA virus characterized by its cytoplasmic site of replication and large subset of genes. Due to the complexity of VACV, the majority of studies focus on the virus rather than the host cell. Thus the repertoire of cell factors and functions required for its replication remain largely unknown. Our previous work to define a subset of these, revealed the cellular degradation machinery as a key requirement of VACV replication. Our findings indicated that ubiquitin (Ub), Ub ligase activity, and proteasome-mediated degradation are required for multiple stages of the virus lifecycle. The aim of this proposal is to reveal how VACV differentially modulates or takes advantage of the Ub proteasome system during genome uncoating, the initiation of DNA replication, and the assembly of progeny virions. For genome uncoating we will characterize the spatial and temporal interactions between ubiquitinated viral proteins, proteasomes, the viral uncoating factor, and the viral genome that occur on cytoplasmic cores. To ascertain how Cullin-3 based ubiquitination and proteasome degradation facilitate the switch from uncoating to replication of the viral genome, we will identify the relevant Cullin-3 substrates in the context of a detailed characterization of viral replication initiation sites. Coming full circle, we will explore the mechanisms used by VACV to modulate cellular degradation such that ubiquitinated viral core proteins are packaged into newly forming virions without being degraded. Using systems biology, virology, cell biology, biochemistry, molecular biology and a wide range of microscopy approaches we will unravel the complex interactions between poxviruses and the host cell degradation machinery. In turn, as viruses often serve as valuable tools to study cell function, this work is likely to uncover new insights into how cells spatially and temporally regulate their own degradative capacities. Ámbito científico natural sciencesbiological sciencesmicrobiologyvirologynatural sciencesphysical sciencesopticsmicroscopysuper resolution microscopynatural sciencesbiological sciencescell biologynatural sciencesbiological sciencesgeneticsgenomesviral genomesmedical and health scienceshealth sciencesinfectious diseasesDNA viruses Programa(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Tema(s) ERC-CoG-2014 - ERC Consolidator Grant Convocatoria de propuestas ERC-2014-CoG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-COG - Consolidator Grant Institución de acogida THE UNIVERSITY OF BIRMINGHAM Aportación neta de la UEn € 516 178,75 Dirección Edgbaston B15 2TT Birmingham Reino Unido Ver en el mapa Región West Midlands (England) West Midlands Birmingham Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 516 178,75 Beneficiarios (2) Ordenar alfabéticamente Ordenar por aportación neta de la UE Ampliar todo Contraer todo THE UNIVERSITY OF BIRMINGHAM Reino Unido Aportación neta de la UEn € 516 178,75 Dirección Edgbaston B15 2TT Birmingham Ver en el mapa Región West Midlands (England) West Midlands Birmingham Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 516 178,75 UNIVERSITY COLLEGE LONDON La participación finalizó Reino Unido Aportación neta de la UEn € 1 753 821,25 Dirección GOWER STREET WC1E 6BT London Ver en el mapa Región London Inner London — West Camden and City of London Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 1 753 821,25