Project description
ER-phagy receptors: mechanisms of remodelling and renewal
The human body is in a continuous state of repair and renewal, from breaking down and reusing damaged or excess cell parts (autophagy) to producing about two million new red blood cells every second. The endoplasmic reticulum (ER) in the cell cytoplasm, critical to the synthesis and transport of cellular components, is no exception. ER-phagy is a major driver of ER remodelling, and ER-phagy receptors play central roles in this process. However, the mechanisms and dynamics of remodelling are largely unknown. The ERC-funded ER-REMODEL project will investigate the role of receptor ubiquitination (attachment of the ubiquitin protein to the receptor) and the formation of ER-phagy receptor clusters in controlling ER-phagy and membrane remodelling.
Objective
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.
Fields of science
Keywords
- 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
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
60323 Frankfurt Am Main
Germany