Molecular Mechanisms of Autophagy and Endoplasmic Reticulum Dynamics

Autophagy is a catabolic mechanism employed by cells to maintain homeostasis and organellar quality control. This degradative system is conserved in eukaryotic organisms, occurs at basal levels and is modulated by stress stimuli. Autophagy is dynamic; it starts with the formation of a double membrane structure (autophagosome), which engulfs portions of the cytosol, and terminates with the fusion of the autophagosome with a lysosome. Autophagy was considered bereaved of substrate specificity; however, we now know there is fine specificity in substrate selection and an intricate molecular mechanism underpinning the process. Our interest is to characterize the molecular mechanisms responsible for ER dynamics during autophagy. The ER is a continuous system of membranes, which are constantly reorganised to fulfil physiological functions. An important aspect is the maintenance of the original ER network, which requires the disassembly and elimination of damaged ER parts. ER membranes are remodeled and removed by selective autophagy, ER-phagy, which is regulated by a subset of specific autophagy receptors. The molecular mechanisms responsible for activation of these receptors and the factors that trigger ER remodeling during autophagy remain largely unexplored. Studying ER dynamics during autophagy is not only important for acquiring new information on a fundamental cellular process but also has major medical implications and therapeutic potential. ER-phagy plays a prominent role in the fight against genetic diseases, cancer and viral infections. The aim of our research is to investigate the involvement of autophagy in ER remodeling; to characterize new ER-phagy receptors and their role in membrane dynamics, and to unravel the molecular mechanisms of ER-related axonal disorders. We plan to approach our scientific questions using state of the art technologies in gene editing (CRISPR-Cas9), proteomics (Mass Spectrometry) and Microscopy.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.