The Function and Regulation of ER-Phagy During ER Homeostasis and Stress
Research area: Protein Folding and Quality Control
Group leaders: Maurizio Molinari
- Carmela Galli Molinari, Scientist
Status: In progress
Autophagy is a conserved cellular process in eukaryotes required for degradation of cytoplasm contents into the lysosome/vacuole. Double-membrane vesicles called autophagosomes mediate the engulfment and transport of the cargo to be degraded during autophagy. While this pathway constitutively degrades cytoplasmic targets, it is also up-regulated by different cellular stresses. Starvation-induced autophagy randomly targets bulk cytoplasmic portions. Additionally, it selectively recognizes and degrades cytoplasmic protein aggregates, damaged organelles or invading microorganisms, playing thus a homeostatic and protective role in the cell. Interestingly, accumulation of misfolded proteins within the ER triggers autophagic degradation of portions of this organelle in yeast and mammals, suggesting that ER-phagy might be a conserved mechanism to prevent or overcome ER stress. While ERAD pathway is the classical and best characterized process for protein disposal in the ER, little is known about the mechanisms underlying ER degradation by autophagy. By using series of stable human cell lines created in our lab expressing regulated amounts of folding-competent and folding-defective protein chimeras, we are studying the contribution of autophagy in the degradation of these putative substrates and the molecular mechanisms regulating such a process. These studies will allow us to characterize the conditions for potential preferences in substrate elimination by ERAD and ER-phagy, and the mechanistic crosstalk between these two pathways and ER stress. The information generated by these studies will be validated in pathological model systems expressing disease-causing folding-defective proteins with the final goal of designing pharmacological treatments targeting protein disposal pathways to alleviate the toxicity caused by aberrant protein accumulation.