We have recently reported that accumulation of mis-folded N-CoR as insoluble protein aggregates in APL cells induces Endoplasmic Reticulum (ER) stress and activates unfolded protein response (UPR). Although, accumulation of mis-folded proteins is known to trigger UPR-induced cytotoxic cell death in several neurodegenerative disorders, APL cells are notably resistant to UPR-induced apoptosis. The molecular basis for the paradoxical response of APL cells to UPR is not known. Here we report that a glyco-protease, selectively expressed in APL cells, regulates APL cells’ response to UPR-induced apoptosis through processing of mis-folded N-CoR protein. Results show that mis-folded N-CoR is cleaved selectively in APL cells, and cellular extracts of APL cells and human primary APL cells contain activity that cleaves N-CoR protein. Purification and spectrometric analysis of N-CoR cleaving activity from an APL cell line reveals that it is a glycoprotein endopeptidase known as OSGEP. Furthermore, the cleavage of N-CoR in APL cells could be blocked by the broad-spectrum protease inhibitor, AEBSF, and by RNAi-mediated down-regulation of OSGEP expression. AEBSF selectively inhibits growth and promotes apoptosis of APL cells, possibly through a mechanism involving AEBSF-induced accumulation of insoluble N-CoR protein and by triggering ER stress. Taken together, these finding suggest that selective induction of protease activity in APL cells may represent a novel cytoprotective component of UPR, which could be exploited by tumor cells to survive the toxic insult of mis-folded protein(s).

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