Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10802992 | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | 2008 | 11 Pages |
Abstract
Calreticulin is a lectin chaperone essential for intracellular calcium homeostasis. Deletion of calreticulin gene compromises the overall quality control within the endoplasmic reticulum (ER) leading to activation of the unfolded protein response. However, the ER structure of calreticulin deficient cells (crtâ/â) is not altered due to accumulation of misfolded proteins. Therefore, the aim of this study was to determine whether the ubiquitin-proteasome pathway is activated in crtâ/â cells as a compensatory mechanism for cell survival. Here we show a significant increase in the expression of genes involved in ER associated degradation and activation of the ubiquitin-proteasome system in crtâ/â cells. We also demonstrated that the ubiquitination of two proteins processed in ER, connexin 43 and A1AT NHK (α1-antitrypsin mutant) are increased in crtâ/â cells. Furthermore, we showed that the increased proteasome activity in the crtâ/â cells could be rescued upon re-introduction of calreticulin or calsequestrin (a muscle calcium binding protein). We also illustrated that increased cytosolic Ca2+ enhances the proteasome activity. Interestingly, suppression of calnexin function using siRNA further elevated the proteasome activity in crtâ/â cells. This is the first report to show that loss of calreticulin function enhances the ubiquitin-proteasome activity which could function as a compensatory mechanism for cell survival.
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Authors
Anton V. Uvarov, Nasrin Mesaeli,