Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1866, Issue 4, Pages 727-736Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2018.12.003
Keywords
Caveolin-1; Calreticulin; Endocytosis; Endoplasmic reticulum stress
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Funding
- NPRP from the Qatar National Research Fund (a member of Qatar Foundation) [4-043-3-016]
- Biomedical Research Program (BMRP)
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Calreticulin an endoplasmic reticulum (ER) chaperone that is involved in the quality control process and plays an important role as a regulator of intracellular calcium homeostasis. Previously, we illustrated that loss of calreticulin (crt-/-) results in the activation of ubiquitin-proteasome pathway facilitating the increased resistance to apoptosis. Our preliminary data illustrated a significant increase in the endocytosis in the calreticulin knockout mouse embryonic fibroblast cells (crt-/-). Therefore, we hypothesized that the mechanism for this increased endocytosis in the crt-/- cells is due to onset of ER stress. To test this hypothesis, we measured endocytosis in the wild type (wt) and crt-/- cells using uptake of fluorescent dextran and showed a significant increase in the rate of its uptake in crt-/- cells as compared to wt cells. To determine the endocytic pathway involved we examined both clathrin and caveolin-1 dependent endocytosis. Our results illustrated no change in the expression of clathrin heavy chain while there was a significant increase in the expression of caveolin-1 in the crt-/- cells as compared to the wt cells. Furthermore, using shRNA we illustrated that knockdown of clathrin heavy chain had no effect on endocytosis in the crt-/- cells. While knock-down of caveolin-1 significantly reduced endocytosis in the crt-/- cells. Finally, we illustrated that a chemical chaperone, 4-phenylbutyrate significantly reduced both the endoplasmic reticulum stress and endocytosis in the crt-/- cells. Our data shows for the first time, that ER stress led to enhanced caveolin-1 mediated endocytosis and reversal of ER stress reduces endocytosis.
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