Spatial ER protein quality control to safeguard proteostasis

A functional proteome relies on cellular machineries for protein synthesis, folding and degradation, collectively known as the proteostasis system.

Spatial sequestration of misfolded proteins into subcellular deposits has emerged as key quality control mechanism for proteins of the cyto- and nucleoplasm. Still, we lack even a rudimentary understanding of spatial quality control of membrane-embedded proteins.

This project aims to unveil a so far unexplored spatial quality control system operating in the endoplasmic reticulum (ER), a biogenesis hub forabout one third of the proteome.

We have found ER-derived membranous compartments that are physically connected to intraluminal buds emerging within the nuclear envelope, likely representing a dynamic sequestration system that immobilizes potentially toxic membrane proteins of the ER and the continuous nuclear membranes.

In an integrated approach based on cell biology, molecular genetics, biochemistry, genome-wide screening and imaging, we will unravel how ER-localized spatial quality control is wired into the network of proteostasis subsystems to safeguard cellular survival.

Specifically, we aim to define cargo origin and identity, map the cellular and molecular networks that control this pathway, and uncover the physiological relevance of this proteostasis subsystem.

In sum, this research will delineate a novel quality control system for membrane-embedded proteins, likely critical for overall proteostasis and cellular fitness.