Summary
Cells control their content by balancing its synthesis and degradation. Autophagy is a key degradation process capable of engulfing large fractions of cells, including organelles, into double-membrane vesicles called autophagosomes. These fuse with lysosomes causing degradation of their cargo. Secretory pathways, including secretory autophagy, offer an alternative option to remove unwanted materials from cells. However, mechanisms allowing the secretion of larger cellular components are still unknown.
We identified a novel pathway, which we termed autoxitus – for self (auto) exit (xitus) – that leads to the secretion of autophagosomes. This proposal aims at defining the molecular mechanism and regulation of autoxitus. We will first study how specificity and decision-making between secretory autoxitus and degradative autophagy routes is achieved and whether there is cross-regulation. Autophagosomes on the autoxitus route can contain parts of the cytosol, but also large fragments of organelles, raising the question whether the secreted autoxitus vesicles signal to neighbouring cells in a non-cell autonomous manner. We aim to uncover the impact of these signalling processes to determine whether and how autoxitus helps to signal stress conditions or may even deliver material or organelles to other cells. Finally, the role of autoxitus in two (patho-)physiological conditions will be analysed. Since autophagic processes are key to viral particle release, we will study the contribution of autoxitus to the viral life cycle. Furthermore, we will investigate the role of autoxitus in the release of protein aggregates from cells and the resulting seeding propensity.
This proposal will give ground-breaking insight into autoxitus, its molecular underpinnings and physiological consequences. AutoXitus will provide the framework for future integration into numerous cellular pathways.
We identified a novel pathway, which we termed autoxitus – for self (auto) exit (xitus) – that leads to the secretion of autophagosomes. This proposal aims at defining the molecular mechanism and regulation of autoxitus. We will first study how specificity and decision-making between secretory autoxitus and degradative autophagy routes is achieved and whether there is cross-regulation. Autophagosomes on the autoxitus route can contain parts of the cytosol, but also large fragments of organelles, raising the question whether the secreted autoxitus vesicles signal to neighbouring cells in a non-cell autonomous manner. We aim to uncover the impact of these signalling processes to determine whether and how autoxitus helps to signal stress conditions or may even deliver material or organelles to other cells. Finally, the role of autoxitus in two (patho-)physiological conditions will be analysed. Since autophagic processes are key to viral particle release, we will study the contribution of autoxitus to the viral life cycle. Furthermore, we will investigate the role of autoxitus in the release of protein aggregates from cells and the resulting seeding propensity.
This proposal will give ground-breaking insight into autoxitus, its molecular underpinnings and physiological consequences. AutoXitus will provide the framework for future integration into numerous cellular pathways.
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| Web resources: | https://cordis.europa.eu/project/id/101125845 |
| Start date: | 01-10-2024 |
| End date: | 30-09-2029 |
| Total budget - Public funding: | 2 000 000,00 Euro - 2 000 000,00 Euro |
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Original description
Cells control their content by balancing its synthesis and degradation. Autophagy is a key degradation process capable of engulfing large fractions of cells, including organelles, into double-membrane vesicles called autophagosomes. These fuse with lysosomes causing degradation of their cargo. Secretory pathways, including secretory autophagy, offer an alternative option to remove unwanted materials from cells. However, mechanisms allowing the secretion of larger cellular components are still unknown.We identified a novel pathway, which we termed autoxitus – for self (auto) exit (xitus) – that leads to the secretion of autophagosomes. This proposal aims at defining the molecular mechanism and regulation of autoxitus. We will first study how specificity and decision-making between secretory autoxitus and degradative autophagy routes is achieved and whether there is cross-regulation. Autophagosomes on the autoxitus route can contain parts of the cytosol, but also large fragments of organelles, raising the question whether the secreted autoxitus vesicles signal to neighbouring cells in a non-cell autonomous manner. We aim to uncover the impact of these signalling processes to determine whether and how autoxitus helps to signal stress conditions or may even deliver material or organelles to other cells. Finally, the role of autoxitus in two (patho-)physiological conditions will be analysed. Since autophagic processes are key to viral particle release, we will study the contribution of autoxitus to the viral life cycle. Furthermore, we will investigate the role of autoxitus in the release of protein aggregates from cells and the resulting seeding propensity.
This proposal will give ground-breaking insight into autoxitus, its molecular underpinnings and physiological consequences. AutoXitus will provide the framework for future integration into numerous cellular pathways.
Status
SIGNEDCall topic
ERC-2023-COGUpdate Date
12-03-2024
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