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Cleavage of Misfolded Nuclear Receptor Corepressor Confers Resistance to Unfolded Protein Response–Induced Apoptosis

¹ Oncology Research Institute, Departments of ² Physiology and ³ Medicine, Yong Loo Lin School of Medicine and ⁴ NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; and ⁵ Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan

Requests for reprints: Matiullah Khan, Oncology Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Clinical Research Center, Block MD11, 10 Medical Drive, Singapore 117597. Phone: 65-6874-8055; Fax: 65-6873-9664; E-mail: nmimmk{at}nus.edu.sg or Shazib Pervaiz. Phone: 65-6874-6602; Fax: 65-6778-8161; E-mail: phssp{at}nus.edu.sg.

We have recently reported that accumulation of misfolded nuclear hormone receptor corepressor (N-CoR) as insoluble protein aggregates in acute promyelocytic leukemia (APL) cells induces endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). Although accumulation of misfolded 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 glycoprotease, selectively expressed in APL cells, regulates the response of APL cells to UPR-induced apoptosis through processing of misfolded N-CoR protein. Results show that misfolded 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 RNA interference–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 findings 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 misfolded protein(s). (Cancer Res 2006; 66(20): 9903-12)

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