Project description
When membranes get overcrowded with proteins
The endoplasmic reticulum (ER) is a complex organelle in terms of both structure and function. It is the largest membrane-bound intracellular compartment, spanning a network of tubules and sheets. The ER plays a critical role in the synthesis of secretory and membrane proteins, their folding, modification, and maturation. At the same time the ER is a major hub for the biosynthesis and distribution of phospholipids and sterols. Dysfunction results in ER stress and a failure to fold soluble and membranes proteins, thereby activating the unfolded protein response (UPR). The UPR is critical to re-establishing homeostasis. Until now, the UPR has been studied with a focus on the role of soluble proteins, whereas the more abundant membrane proteins have been largely overlooked. All that is changing with the EU-funded MemDense project, which studies the role of the density of ER membrane proteins and their misfolding in adaptive responses.
Objective
All cells must balance the production of proteins and lipids to maintain membrane functions. Imbalances in protein folding and lipid metabolism cause endoplasmic reticulum (ER) stress associated with a wide range of complex diseases including diabetes, neurodegeneration, and viral infections. The central homeostatic program of the ER is the unfolded protein response (UPR), which senses unfolded proteins in the ER to control protein synthesis, chaperone abundance, and lipid metabolism. Through these mechanisms, the UPR centrally controls decisions between cell survival, adaptation, and apoptosis. The field has focused almost exclusively on soluble proteins as triggers of the UPR, while the more abundant membrane proteins have been neglected. Our finding of UPR activation by membrane aberrancies provides a radically new perspective and allows us to address central questions in membrane and cell biology: How is the density of ER membrane proteins sensed and controlled? How are misfolded membrane proteins recognized to mount adaptive responses?
Focusing on the conceptual advance that UPR transducers sense signals from the membrane, we will 1) establish and reconstitute the machinery for sensing membrane protein crowding, 2) identify mechanisms coordinating protein and lipid homeostasis between organelles, 3) study the molecular recognition of misfolded membrane proteins by the UPR.
Key to this endeavor is our unique combination of genetic, biochemical, and biophysical tools for parallel characterization of the UPR in vivo and in vitro. Combining this framework with novel strategies for an immuno-isolation of organelles, we are primed to answer how membrane aberrancies cause chronic ER stress. By establishing the UPR as a quality control system for membrane proteins, and providing novel tools and valuable resources to the community, MemDense will have wide impact on our molecular and cellular understanding of ER homeostasis and the many diseases related to ER stress.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine endocrinology diabetes
- natural sciences biological sciences biochemistry biomolecules lipids
- medical and health sciences basic medicine physiology homeostasis
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2019-COG
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66123 Saarbrucken
Germany
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