Loss of calreticulin function decreases NFκB activity by stabilizing IκB protein

Transcription factor NF kappa B 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 NF kappa B signaling thus contributing to enhanced resistance to apoptosis. In contrast to our hypothesis, we observed a significant decrease in the basal transcriptional activity of NF kappa B in CRT-deficient cells. Treatment with lipopolysaccharide failed to increase the transcriptional activity of NF kappa B in the crt(-/-) cells to the same level as in the wt cells. Our data illustrate that the mechanism of decreased NE kappa B activity in CRT-deficient cells is mediated by a significant increase in I kappa B protein expression. Furthermore, we showed a significant increase in protein phosphatase 2A activity inhibition which resulted in decreased I kappa B alpha protein level in CRT-deficient cells. Based on our data we concluded that loss of CRT increases the stability of I kappa B protein thus reducing NF kappa B activity. (C) 2014 Elsevier B.V. All rights reserved.