Cellular control of membrane protein density in the endoplasmic reticulum via the unfolded protein response - MemDense

Programme(s): H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)

Topic(s): ERC-2019-COG - ERC Consolidator Grant

Call for proposal: ERC-2019-COG

Funding Scheme: ERC-COG - Consolidator Grant

Grant agreement ID: 866011

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.