title: Cleavage of misfolded nuclear receptor corepressor confers resistance to unfolded protein response-induced apoptosis.
abstract: 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).
authors.affiliation: Oncology Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Angela Ping Ping
authors.initials: AP
authors.lastname: Ng
authors.forename: Jek
authors.initials: J
authors.lastname: Howe Fong
authors.forename: Dawn
authors.initials: D
authors.lastname: Sijin Nin
authors.forename: Jayshree L
authors.initials: JL
authors.lastname: Hirpara
authors.forename: Norio
authors.initials: N
authors.lastname: Asou
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
authors.forename: Matiullah
authors.initials: M
authors.lastname: Khan
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D004492:Edetic Acid / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008666:Metalloendopeptidases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D011480:Protease Inhibitors / Q000494:pharmacology; D017510:Protein Folding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D020298:U937 Cells
chemical_list: C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011480:Protease Inhibitors; D012097:Repressor Proteins; D013450:Sulfones; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D004492:Edetic Acid; D008666:Metalloendopeptidases; C070738:O-sialoglycoprotein endopeptidase