Reflux of Endoplasmic Reticulum proteins to the cytosol inactivates tumor suppressors

Daria Sicari, Federica G. Centonze, Raphael Pineau, Pierre Jean Le Reste, Luc Negroni, Sophie Chat, M. Aiman Mohtar, Daniel Thomas, Reynald Gillet, Ted Hupp, Eric Chevet, Aeid Igbaria

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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).

Original languageEnglish
Article numbere51412
JournalEMBO Reports
Issue number5
StatePublished - 5 May 2021


  • ER stress
  • ERAD
  • cancer
  • endoplasmic reticulum
  • reflux

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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