# Membrane Contact Sites in Proteostasis and ER Stress Response

## TL;DR

This paper explores how membrane contact sites help maintain protein health and manage stress in cells, focusing on interactions between the endoplasmic reticulum and endolysosomes.

## Contribution

The paper introduces new insights into how membrane contact sites coordinate organelle interactions to manage protein quality and stress.

## Key findings

- Membrane contact sites facilitate communication between the endoplasmic reticulum and endolysosomes for protein quality control.
- ER-phagy and proteasomal degradation pathways are regulated through these specialized interfaces.
- Dysfunction in these processes is linked to diseases involving disrupted membrane homeostasis.

## Abstract

Execution of all cellular functions depends on a healthy proteome, whose maintenance requires multimodal oversight. Roughly a third of human proteins reside in membranes and thus present unique topological challenges with respect to biogenesis and degradation. To meet these challenges, eukaryotes have evolved organellar pathways of protein folding and quality control. Most transmembrane proteins originate in the endoplasmic reticulum (ER), where they are subject to surveillance and, if necessary, removal through either ER-associated proteasomal degradation (cytosolic pathway) or selective autophagy (ER-phagy; organellar pathway). In the latter case, ER cargoes are shuttled to (endo)lysosomes – the same organelles that degrade cell surface molecules via endocytosis. Here, we provide an overview of dynamic coordination between the ER and endolysosomes, with a focus on their engagement in specialized physical interfaces termed membrane contact sites (MCSs). We cover how cross-compartmental integration through MCSs allows biosynthetic and proteolytic organelles to fine-tune each other's membrane composition, organization, and dynamics and facilitates recovery from proteotoxic stress. Along the way, we highlight recent developments and open questions at the crossroads between organelle biology and protein quality control and cast them against the backdrop of factor-specific diseases associated with perturbed membrane homeostasis.