title: Loss of calreticulin function decreases NFκB activity by stabilizing IκB protein.
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 Ca(2+)-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.
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College Qatar, Doha, Qatar.
authors.forename: Hamid
authors.initials: H
authors.lastname: Massaeli
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Jalali
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College Qatar, Doha, Qatar.
authors.forename: Divya
authors.initials: D
authors.lastname: Viswanathan
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Biochemistry, Weill Cornell Medical College Qatar, Doha, Qatar. Electronic address: nam2033@qatar-med.cornell.edu.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Mesaeli
keywords: Calreticulin; IκB; NFκB; Okadaic acid; PP2A