Endoplasmic reticulum remodelling via ER-phagy pathways

Introduction

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.

ER-Phagy Receptors

By linking the ER membrane to the autophagic machinery, ER-phagy receptors play central roles in this process. However, beyond the identities of ER-phagy receptors, we have little understanding of the mechanisms underlying ER-phagy and the dynamics of ER remodelling.

Research Objectives

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:

1. Site-specific receptor ubiquitination
2. Formation of ER-phagy receptor clusters

Particularly, we will investigate how ubiquitination regulates cluster size, dynamics, localization, identity, and composition.

Methodology

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.

Expected Outcomes

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 the pathophysiology of human diseases, from bacterial infections to neurological disorders.

Significance

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.