1. A novel apoptotic pathway in quiescent lymphocytes identified by inhibition of a post-proline cleaving aminodipeptidase: a candidate target protease, quiescent cell proline dipeptidase.
- Author
-
Chiravuri M, Schmitz T, Yardley K, Underwood R, Dayal Y, and Huber BT
- Subjects
- Apoptosis drug effects, Boronic Acids metabolism, Caspases metabolism, Cell Death drug effects, Cell Death immunology, Cysteine Endopeptidases metabolism, Dipeptidases metabolism, Dipeptidyl Peptidase 4 metabolism, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Humans, Hydrolysis, Interphase drug effects, Interphase immunology, Lymphocytes drug effects, Lymphocytes ultrastructure, Microscopy, Electron, Multienzyme Complexes metabolism, Proline analogs & derivatives, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational drug effects, Resting Phase, Cell Cycle immunology, Substrate Specificity immunology, Apoptosis immunology, Dipeptidases antagonists & inhibitors, Lymphocytes enzymology, Proline metabolism, Protein Processing, Post-Translational immunology
- Abstract
The vast majority of lymphocytes in vivo persist in a quiescent state. These resting lymphocytes are maintained through a cellular program that suppresses apoptosis. We show here that quiescent PBMC, but not activated PBMC or transformed lymphocytes, die in the presence of highly specific post-proline aminodipeptidase inhibitors. This form of death has the hallmarks of apoptosis, such as phosphatidylserine externalization and loss of mitochondrial transmembrane potential. However, it differs from apoptosis induced by gamma irradiation in the same cells or by Fas ligation in transformed lymphocytes in terms of caspase involvement. In addition, the aminodipeptidase inhibitor-induced cell death, but not gamma-irradiation-mediated apoptosis, can be prevented by inhibition of the proteasome complex. The target of these inhibitors is not CD26/DPPIV, but probably a novel serine protease, quiescent cell proline dipeptidase, that we have recently isolated and cloned. These studies will yield a better understanding of the requirements and the mechanisms that mediate quiescent lymphocyte homeostasis in vivo.
- Published
- 1999