Interaction with XIAP prevents full caspase-3/-7 activation in proliferating human T lymphocytes

• Published in: European journal of immunology 2008-07, Vol.38 (7), p.1979-1987
• Main Authors: Paulsen, Maren, Ussat, Sandra, Jakob, Marten, Scherer, Gudrun, Lepenies, Inga, Schütze, Stefan, Kabelitz, Dieter, Adam-Klages, Sabine
• Format: Article
• Language: English
• Subjects: Apoptosis; Caspase 3 - metabolism; Caspase 7 - metabolism; Caspases; Cell Proliferation; Enzyme Activation; Humans; Lymphocyte Activation; Proliferation; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T lymphocytes; X-Linked Inhibitor of Apoptosis Protein - metabolism; XIAP
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200838211

Caspases are essential mediators of cytokine release and apoptosis. Additionally, caspase activity is required for the proliferation of naive T lymphocytes. It remained unclear how proliferating cells are able to cope with the pro-apoptotic activity especially of effector caspases-3 and -7. Possible reasons might include limited subcellular localization of active caspases or inhibition by endogenous caspase inhibitors. Here, we compared the activation of various caspases in proliferating human T cells with that in apoptotic cells. We show that cleaved caspases-3/-7 appear to be widely distributed in apoptotic cells while they are largely confined to the cytoplasm in proliferating cells. Additionally, in proliferating T cells caspase-3 remains incompletely cleaved, while in apoptotic cells fully mature caspase-3 is generated. We provide evidence that during T cell proliferation the intracellular caspase inhibitor X-linked inhibitor-of-apoptosis protein (XIAP) interacts with caspases-3/-7, thereby blocking their full activation, substrate cleavage, and cell death. The lack of substrate cleavage might also lead to the observed limited subcellular distribution of caspases-3/-7. After induction of apoptosis, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low isoelectric point (Smac/DIABLO) is released from mitochondria, resulting in the abrogation of the inhibitory effect of XIAP, full activation of caspases-3/-7, and apoptosis.