Endoplasmic reticulum stress enhances endocytosis in calreticulin deficient cells

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Abstract

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.

Original languageEnglish
Pages (from-to)727-736
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number4
DOIs
Publication statusPublished - Apr 2019

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Keywords

  • Calreticulin
  • Caveolin-1
  • Endocytosis
  • Endoplasmic reticulum stress

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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