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Reflux of Endoplasmic Reticulum proteins to the cytosol inactivates tumor suppressors
Author(s) -
Sicari Daria,
Centonze Federica G,
Pineau Raphael,
Le Reste PierreJean,
Negroni Luc,
Chat Sophie,
Mohtar M Aiman,
Thomas Daniel,
Gillet Reynald,
Hupp Ted,
Chevet Eric,
Igbaria Aeid
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202051412
Subject(s) - cytosol , endoplasmic reticulum , proteostasis , microbiology and biotechnology , suppressor , unfolded protein response , biology , endoplasmic reticulum associated protein degradation , biochemistry , enzyme , gene
In the past decades, many studies reported the presence of endoplasmic reticulum (ER)‐resident proteins in the cytosol. However, the mechanisms by which these proteins relocate and whether they exert cytosolic functions remain unknown. We find that a subset of ER luminal proteins accumulates in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells, ER protein reflux to the cytosol occurs upon ER proteostasis perturbation. Using the ER luminal protein anterior gradient 2 (AGR2) as a proof of concept, we tested whether the refluxed proteins gain new functions in the cytosol. We find that refluxed, cytosolic AGR2 binds and inhibits the tumor suppressor p53. These data suggest that ER reflux constitutes an ER surveillance mechanism to relieve the ER from its contents upon stress, providing a selective advantage to tumor cells through gain‐of‐cytosolic functions—a phenomenon we name ER to Cytosol Signaling (ERCYS).