ER residential chaperone GRP78 unconventionally relocalizes to the cell surface via endosomal transport.

Abstract

Despite new advances on the functions of ER chaperones at the cell surface, the translocation mechanisms whereby these chaperones can escape from the ER to the cell surface are just emerging. Previously we reported that in many cancer types, upon ER stress, IRE1α binds to and triggers SRC activation resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. In this study, using a combination of molecular, biochemical, and imaging approaches, we discovered that in colon and lung cancer, upon ER stress, ER chaperones, such as GRP78 bypass the Golgi and unconventionally traffic to the cell surface via endosomal transport mediated by Rab GTPases (Rab4, 11 and 15). Such unconventional transport is driven by membrane fusion between ER-derived vesicles and endosomes requiring the v-SNARE BET1 and t-SNARE Syntaxin 13. Furthermore, GRP78 loading into ER-derived vesicles requires the co-chaperone DNAJC3 that is regulated by ER-stress induced PERK-AKT-mTOR signaling.

• Authors: Richard Van Krieken, Yuan-Li Tsai, Anthony J Carlos, Dat P Ha, Amy S Lee
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 78 Issue 12 Pg. 5179-5195 (Jun 2021) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 33974094 (Publication Type: Journal Article)

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins

Topics

• Cell Membrane (metabolism)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Golgi Apparatus (metabolism)
• Heat-Shock Proteins (genetics, metabolism)
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Mutagenesis, Site-Directed
• Mutation
• Protein Transport
• Signal Transduction
• Tumor Cells, Cultured