Loss of calreticulin function decreases NFκB activity by stabilizing IκB protein

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Abstract

Transcription factor NFκB is activated by several processes including inflammation, endoplasmic-reticulum (ER) stress, increase in Akt signaling and enhanced proteasomal degradation. Calreticulin (CRT) is an ER Ca2+-binding chaperone that regulates many cellular processes. Gene-targeted deletion of CRT has been shown to induce ER stress that is accompanied with a significant increase in the proteasome activity. Loss of CRT function increases the resistance of CRT-deficient (crt-/-) cells to UV- and drug-induced apoptosis. Based on these reports we hypothesized that loss of CRT will activate NFκB signaling thus contributing to enhanced resistance to apoptosis. In contrast to our hypothesis, we observed a significant decrease in the basal transcriptional activity of NFκB in CRT-deficient cells. Treatment with lipopolysaccharide failed to increase the transcriptional activity of NFκB in the crt-/- cells to the same level as in the wt cells. Our data illustrate that the mechanism of decreased NFκB activity in CRT-deficient cells is mediated by a significant increase in IκB protein expression. Furthermore, we showed a significant increase in protein phosphatase 2A activity inhibition which resulted in decreased IκBα protein level in CRT-deficient cells. Based on our data we concluded that loss of CRT increases the stability of IκB protein thus reducing NFκB activity.

Original languageEnglish
Pages (from-to)2385-2393
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1843
Issue number11
DOIs
Publication statusPublished - Nov 2014

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Keywords

  • Calreticulin
  • IκB
  • NFκB
  • Okadaic acid
  • PP2A

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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