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Inhibitor of Apoptosis Protein hILP Undergoes Caspase-mediated Cleavage during T Lymphocyte Apoptosis¹

Departments of Pathology [E. W., G-Q. W., A. A., H. R.], Pharmacology [D. E. J.], Medicine [D. E. J., S. M. D.], and Otolaryngology [B. R. G.], University of Pittsburgh School of Medicine, University of Pittsburgh Mass Spectrometry Facility [A. A.], and University of Pittsburgh Cancer Institute [D. E. J., H. R.], Pittsburgh, Pennsylvania 15123

Several endogenous or viral inhibitors of apoptosis, including Bcl-2, Bcl-x_L, FLIP, p35, and CrmA, have been shown to be cleaved by caspases during apoptosis. In this study, we demonstrate that the endogenous inhibitor of apoptosis, hILP/XIAP, is also cleaved in apoptotic T lymphocytes, generating at least one prominent fragment of 29 kDa. This p29 cleaved fragment was detected in Jurkat cells induced to apoptose by anti-Fas antibody, staurosporin, or VP-16. The cleavage of hILP appears to be caspase mediated because the production of the p29 protein was inhibited by the pan-caspase peptide inhibitor, Z-VAD.FMK. In Jurkat cells engineered to overexpress CrmA, cleavage of hILP in response to anti-Fas antibody or staurosporin was inhibited, whereas overexpression of Bcl-2 abrogated the cleavage in response to VP-16. Cleavage of hILP was also observed in cell-free reactions using in vitro translated hILP and recombinant caspase-3 or -7. Moreover, we found that the p29 hILP fragment retained the ability to bind caspase-3 and -7, as shown previously for full-length or BIR-2 hILP. The p29 cleavage product was also detected during T-cell receptor-mediated apoptosis in peripheral blood lymphocytes from normal donors. Furthermore, tumor-associated T lymphocytes purified from ascites of patients with ovarian cancer expressed fragmented hILP, which was not detected in control T cells purified from peripheral blood of normal donors. Our results suggest that the cleavage of hILP represents an important event in apoptosis of T lymphocytes in both normal and pathological in vivo settings.

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