Descrizione del progetto
Recettori dell’ER-fagia: meccanismi di rimodellamento e rinnovamento
Il corpo umano è in uno stato continuo di riparazione e rinnovamento, dalla rottura e riutilizzo di parti di cellule danneggiate o in eccesso (autofagia) alla produzione di circa due milioni di nuovi globuli rossi al secondo. Il reticolo endoplasmatico (ER) nel citoplasma cellulare, fondamentale per la sintesi e il trasporto dei componenti cellulari, non fa eccezione. L’ER-fagia è uno dei principali motori del rimodellamento dell’ER e i suoi recettori svolgono un ruolo centrale in questo processo. Tuttavia, i meccanismi e le dinamiche del rimodellamento sono in gran parte sconosciuti. Il progetto ER-REMODEL, finanziato dal CER, studierà il ruolo dell’ubiquitinazione del recettore (attaccamento della proteina ubiquitina al recettore) e la formazione di cluster di recettori dell’ER-fagia nel controllo dell’ER-fagia e del rimodellamento della membrana.
Obiettivo
The endoplasmic reticulum (ER) is the most extensive endomembrane system of the cell that undergoes continuous remodelling and adaptation to fulfil required functions in synthesis and transport of cellular components. A major driver of ER remodelling is ER-phagy, a selective autophagy pathway that targets excess or damaged portions of ER for degradation. By linking the ER membrane to the autophagic machinery, ER-phagy receptors play central roles in this process. However, beyond the identities of ER-phage receptors, we have little understanding of the mechanisms underlying ER-phagy and the dynamics of ER remodelling. This proposal aims to decipher the mechanisms by which ER-phagy receptors, especially those containing reticulon-homology domains (RHD), drive the dynamic process of ER remodelling in a cell-type specific fashion. We will determine how ER-phagy is regulated by site-specific receptor ubiquitination and by the formation of ER-phagy receptor clusters, particularly how ubiquitination regulates cluster size, dynamics, localization, identity and composition. We will combine structural, computational and functional approaches to determine, at the highest possible resolution, how ubiquitination and clustering of ER-phagy receptors controls the multistep process of ER-phagy and membrane remodelling. We aim for a comprehensive understanding of the distinct mechanisms involved in ER remodelling in different cell types and in response to various stress conditions. This mechanistic knowledge is essential to explain how changes in ER-phagy and ER remodelling impact on the pathophysiology of human diseases from bacterial infections to neurological disorders. These novel and ground-breaking discoveries will elucidate an ER-phagy receptor code controlling ER remodelling in health and disease. Moreover, ER-REMODEL will provide a conceptual framework for future studies into the dynamic regulation of other cellular organelles via ubiquitin-driven selective autophagy.
Campo scientifico
Parole chiave
- ER-phagy
- ER Remodelling
- ER Stress
- Cellular Homeostasis
- Reticulons
- Reticulon Homology Domain
- Ubiquitination
- Membrane Dynamics
- Autophagy
- Neurodegeneration
- Legionella
- Molecular Simulations
- Disease Modelling
- qProteomics
- Cell Biology
- Post-translational Modifications
- Structural Biology
- Receptor Clustering
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
60323 Frankfurt Am Main
Germania