Recognition and removal of organelle damage at the endoplasmic reticulum membrane

• Applicant: Professor Dr. Sebastian Schuck
• Subject Area: Biochemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455429207

Cells employ numerous quality control mechanisms to ensure organelle integrity. Compared to quality control in the cytosol, quality control of membrane-enclosed organelles poses unique challenges. Organelle membranes present barriers for the detection and elimination of damaged proteins, yet these barriers need to be maintained at all times. The endoplasmic reticulum (ER) is a central protein folding compartment liable to the accumulation of misfolded proteins. In earlier work, we focused on two related quality control mechanisms in yeast that respond to ER stress. First, we showed that selective microautophagy of ER (micro-ER-phagy) involves the formation of multi-lamellar ER whorls that are degraded in lysosomes, presumably to remove ER damage. We recently found that ESCRT proteins are essential for micro-ER-phagy because they mediate lysosomal membrane fission to complete microautophagy of whorls. We also found that the control of protein entry into whorls likely is critical for the selectivity of micro-ER-phagy. Second, we discovered that ER stress triggers a striking recruitment of ESCRT proteins to morphologically aberrant ER subdomains. We call this mechanism REMED (Recruitment of ESCRT Machinery to sites of ER Damage). We hypothesize that REMED repairs ER membrane damage and cooperates with micro-ER-phagy. Here, we propose to investigate the mechanisms of micro-ER-phagy and REMED, and explore the functional links between them. In Aim 1, we will apply proteomic approaches to determine the protein contents of ER whorls and thus define cargo selectivity. In Aim 2, we will elucidate the mechanism of REMED through yeast genetic screens and cell biological experiments, and ask whether REMED exists in human cells. In Aim 3, we will use genetic interaction studies and functional assays in yeast to understand the physiological roles of micro-ER-phagy and REMED. This project will yield new insight into ER damage recognition and removal. Moreover, given that manipulating ER quality control promises health benefits, our research may identify new therapeutic approaches.

• DFG Programme: Research Grants