Cleavage of misfolded nuclear receptor corepressor confers resistance to unfolded protein response-induced apoptosis.
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).
Ng
Angela Ping Ping
AP
Oncology Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Howe Fong
Jek
J
Sijin Nin
Dawn
D
Hirpara
Jayshree L
JL
Asou
Norio
N
Chen
Chien-Shing
CS
Pervaiz
Shazib
S
Khan
Matiullah
M
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
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