Project Title Unraveling the Mysteries of ER-phagy: Exploring the Intricate Pathways of ER Stress-Induced ER-phagy

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The Endoplasmic Reticulum (ER) is a remarkable organelle with multifaceted functions, serving as the epicenter of protein synthesis, modification, and inter-organelle communication. It collaborates extensively with mitochondria, lysosomes, and the plasma membrane, facilitating the transport of vital metabolites, lipids, and proteins. Recent studies, including our own research, have shed light on a process called ER-phagy, wherein the ER undergoes targeted degradation through autophagy in response to various stressors such as amino acid deprivation, protein misfolding, and cellular differentiation(1,2). Our recent data suggest that ER-phagy also acts as a backup pathway to the proteasome-mediated ER-associated degradation (ERAD) pathway during ER stress and its activity is amplified when ERAD is inhibited. However, the underlying mechanism and crosstalk between ERAD and ER-phagy remain unclear and forms the basis of this PhD project. This potential outcome of this work is particularly exciting and could hint towards leveraging ER-phagy activation as an alternative strategy in diseases related to ERAD defects ranging from obesity and metabolic disorders, to neurodegenerative diseases and polyglutamine diseases. In this PhD project, we aim to identify and characterize novel key players involved in stimulus-induced ER-phagy, with the ultimate goal of shedding light on both the physiological roles and pathological consequences of ER-phagy. Building upon our established assays and preliminary data, we aim to address the following questions: What are the fundamental components orchestrating ER stress-induced ER-phagy? Using genetics, biochemistry, and mass spectrometry, we will delve into the molecular landscape to uncover the critical players responsible for initiating and executing ER-phagy. How are these key players regulated and activated in response to stress? How are these key players regulated and activated in response to stress? We will use proteomics and gene expression analysis to understand the post-translational modifications and regulatory networks that govern ER-phagy What is the overall implication of failed ER-phagy? By investigating the repercussions of impaired ER-phagy, we will gain a deeper understanding of the pathological outcomes and potential disease associations resulting from aberrant ER-phagy processes.