Endoplasmic-Reticulum to CYtosol Signaling (ERCYS): Inter-organellar communication associated with cancer chemoresistance

Cellular organelles are contained within membranes that isolate their content from other cellular compartments. Each cellular organelle exhibits specific characteristics with select protein contents, redox potential, pH, and dedicated roles. In order to keep the cell`s functionality, these cellular compartments have to communicate and coordinate their functions. In the past three decades, many studies have reported that in the frame of several human diseases (e.g., cancer and neurodegenerative diseases), a subset of endoplasmic reticulum (ER) resident proteins accumulates in the cytosol. Recently, we discovered a novel ER surveillance mechanism that debulks the ER during stress to restore homeostasis through chaperone-mediated ER protein reflux to the cytosol. We showed that ER stress-mediated protein reflux is a conserved protein quality control process from yeast to mammals and plays an essential role in tumors from human patients (Glioblastoma) and murine models. We named this mechanism ER-to-Cytosol-Signaling (ERCYS). ERCYS represents a selective advantage in cancer cells by maintaining proper secretory functions and cytosolic gain-of-functions, leading to increased cell fitness and inactivating tumor suppressors in the cytosol. In Summary, ER stress-dependent signaling that relies on dynamic protein redistribution between the ER and the cytosol might constitute an adaptive feature in the development of various human diseases, including cancer.