Abstract

In the past decades many studies reported Endoplasmic Reticulum (ER) resident proteins to localize to the cytosol but the mechanisms by which this occurs and whether these proteins exert cytosolic functions remain unknown. We found that select ER luminal proteins accumulate in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells ER protein reflux to the cytosol occurs upon proteostasis perturbation. As such we investigated whether refluxed proteins gain new functions in the cytosol thus providing advantage to tumor cells. Using the ER luminal protein AGR2 as a model, we showed that it is refluxed to the cytosol where it binds and inhibits the tumor suppressor p53. We named this phenomenon ER to Cytosol Signaling (ERCYS) as an ER surveillance mechanism conserved in Eukaryotes to relieve the ER from its contents upon stress and to provide selective advantage to tumor cells through gain-of-cytosolic functions.