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Contenido archivado el 2024-05-27

The Role of Atg8 Posttranslational Modifications in Autophagy

Objetivo

"Autophagy is an important cellular degradation pathway required for eukaryotic protein homeostasis. Deregulation of autophagy has been shown to cause the development of various human pathologies, including aggregation diseases and cancer. Autophagy involves the formation of double-membrane vesicles, called autophagosomes, which sequester portions of the cytosol (general autophagy) or whole protein aggregates, organelles or pathogens (selective autophagy). Autophagosomes then fuse with the lysosome or vacuole, where the cargo is degraded. Atg8 is a key regulator of autophagy facilitating autophagosome formation, lysosomal fusion and cargo recruitment. Atg8 is conjugated to the lipid phosphatidylethanolamine and is thereby inserted into the arising autophagsomal membrane, in which it promotes autophagosomal membrane expansion and cargo recruitment through direct binding of LIR-motif containing cargo adaptors.
Interestingly, large-scale proteomics data suggest that Atg8 is regulated by several posttranslational modifications (PTMs). Here we propose to study the functional implications of these Atg8 modifications for general and selective autophagy. Intriguingly, our preliminary data suggest that Atg8 undergoes Atg1- and Atg7-dependent polyubiquitination. We propose that Atg8 polyubiquitination may cause a switch from selective to general autophagy to promote cell survival or, alternatively, that it may play a role in autophagosome-vacuole fusion. Moreover, we will investigate the enzymatic machinery and regulatory mechanisms underlying Atg8 PTMs. We anticipate bridging the knowledge gap between large-scale proteomics data and essential functional and mechanistic understanding of Atg8 PTMs. Based on our promising preliminary data, we are confident that this study will provide important insights into the regulation of autophagy while also contributing to the identification of novel drug targets for the treatment of autophagy-related diseases."

Convocatoria de propuestas

FP7-PEOPLE-2012-IEF
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Coordinador

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Aportación de la UE
€ 184 709,40
Dirección
Raemistrasse 101
8092 Zuerich
Suiza

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Región
Schweiz/Suisse/Svizzera Zürich Zürich
Tipo de actividad
Higher or Secondary Education Establishments
Contacto administrativo
Matthias Peter (Prof.)
Enlaces
Coste total
Sin datos