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In Situ Monitoring of Transiently Formed Molecular Chaperone Assemblies in Bacteria, Yeast, and Human Cells
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ER residential chaperone GRP78 unconventionally relocalizes to the cell surface via endosomal transport

Richard Van Krieken1, Yuan-Li Tsai1, Anthony J Carlos1

  • 1Department of Biochemistry and Molecular Medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave., NOR 5308, Los Angeles, CA, 90089-9176, USA.

Cellular and Molecular Life Sciences : CMLS
|May 11, 2021
PubMed

Insights

Cancer cells utilize unconventional ER chaperone transport to reach the cell surface. This pathway, mediated by Rab GTPases and specific SNAREs, bypasses the Golgi during ER stress, offering new therapeutic targets.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Emerging evidence highlights the cell surface functions of endoplasmic reticulum (ER) chaperones.
  • Mechanisms for ER chaperone translocation to the cell surface remain largely unknown.
  • Previous work implicated IRE1α, SRC activation, and Golgi disruption in ER chaperone cell surface expression.

Purpose of the Study:

  • To elucidate the translocation mechanisms of ER chaperones to the cell surface.
  • To investigate the role of endosomal transport in ER chaperone trafficking during ER stress.
  • To identify key molecular players involved in this unconventional pathway.

Main Methods:

  • Molecular biology techniques
  • Biochemical assays
  • Advanced imaging approaches

Main Results:

  • ER chaperones, like GRP78, traffic unconventionally to the cell surface via endosomal pathways in colon and lung cancer.
  • This transport is mediated by Rab GTPases (Rab4, 11, 15) and requires ER-derived vesicle fusion with endosomes.
  • Vesicular transport involves v-SNARE BET1 and t-SNARE Syntaxin 13.
  • GRP78 loading into vesicles is regulated by DNAJC3, which is controlled by PERK-AKT-mTOR signaling during ER stress.

Conclusions:

  • Discovered an unconventional, Golgi-bypass route for ER chaperone cell surface translocation.
  • Identified key molecular mediators including Rab GTPases, SNAREs, and DNAJC3.
  • This pathway is regulated by ER stress signaling and offers potential therapeutic targets in cancer.
Keywords:
Endoplasmic reticulum stressEndosomeGRP78Unconventional trafficking

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