The endoplasmic reticulum (ER) plays a central role in protein folding, modification, and secretion. Perturbations in these processes trigger ER stress and activate the unfolded protein response (UPR), a signaling network that aims to restore ER homeostasis. Dysregulation of ER homeostasis contributes to a wide range of pathologies, including cancer, tissue fibrosis, metabolic disorders, and neurodevelopmental defects. ER quality control is also maintained by the proteasome (via ER-associated degradation, ERAD) and the autolysosome (via ER-specific autophagy, ER-phagy)^1-3. Together, the UPR, ERAD, and ER-phagy coordinate ER quality control to safeguard cellular function.

Whereas the UPR is canonically known to activate ERAD, our recent unpublished data indicate that UPR signaling represses ER-phagy activity. This observation has strong implications for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, where antibody hyperproduction drives chronic ER stress and aberrant UPR activation. We hypothesize that the UPR–ER-phagy axis could represent a therapeutic target, enabling rerouting of excess antibody cargo towards autophagic degradation rather than secretion.

The aim of this PhD project is to elucidate the molecular mechanisms by which UPR signaling regulates ER-phagy and to investigate the physiological relevance of this crosstalk in autoimmune disease models. The project will employ disease-relevant immune cell systems to explore the feasibility of activating ER-phagy to promote degradation of ER proteins, including misfolded aggregates and antibodies.

The successful candidate will receive extensive training in state-of-the-art methodologies, including CRISPR-based genome engineering and genome-wide screening, mammalian cell culture, live-cell imaging, flow cytometry, proteomics, and advanced biochemical and molecular biology techniques. They will also benefit from access to disease-relevant models and a highly collaborative research environment within the School of Life Sciences at the University of Dundee.

  Biography:  

1. Liang, JR and Corn, JE 2022. A CRISPR view on autophagy. Trends in Cell Biology.  
2. Liang JR, Lingeman E, Luong T, Ahmed S, Muhar M, Nguyen T, Olzmann JA, Corn JE (2019) A genome-wide screen for ER autophagy highlights key roles of mitochondrial metabolism and ER-resident UFMylation Cell 180 1160-1177  
3. Liang JR, Lingeman E, Ahmed S, Corn JE (2018) Atlastins remodel the endoplasmic reticulum for selective autophagy. Journal of Cell Biology J Cell Biol 217 3354-3367