Abstract
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).
Highlights
The endoplasmic reticulum (ER) is the gateway to the secretory pathway maintaining the communication between the cell’s intracellular space and extracellular environment
In addition to ER quality control (ERQC) and ER-associated degradation (ERAD), a pre-emptive quality control mechanism was described that averts protein entry into the secretory pathway under protein-folding stress resulting in their proteasomal degradation in the cytosol (Kang et al, 2006)
We focused on Anterior GRadient 2 (AGR2, PDIA17) that was highly enriched in the digitonin fractions upon ER stress (Fig 5A and Appendix Fig S3A–C)
Summary
The endoplasmic reticulum (ER) is the gateway to the secretory pathway maintaining the communication between the cell’s intracellular space and extracellular environment. Individual tumors exhibited heterogenous refluxed protein patterns, which might reflect inter-tumor heterogeneity (Fig 1F and G) In both GBM tumors (human- or murine-derived, N-linked-glycoproteins (such as ERDJ3/DNAJB11) were found in the digitonin fraction indicating that the refluxed proteins had been translocated into the ER and modified by N-Linked glycosylation, before being refluxed to the cytosol (Appendix Fig S1G-H). These data indicate that in GBM, ER protein reflux might be selectively regulated by different factors such as tumor heterogeneity, genetic background, or activation status of UPR.
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