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Caspase-mediated Degradation of T-Cell Receptor -Chain¹

Departments of Pathology [T. L. W., H. R.], Pharmacology [D. E. J.], Medicine [D. E. J.], and Otolaryngology [B. R. G., T. L. W.], University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute [D. E. J., T. L. W., H. R.], Pittsburgh, Pennsylvania 15213

We recently reported an association between loss in T-cell receptor (TcR) -chain expression and tumor-induced apoptosis of T lymphocytes. In this study, the possibility that -chain serves as a direct substrate for activated caspases was investigated. Here, we report that two DXXD motifs, which are putative recognition sequences for caspase-3-related proteases and are present in the amino acid sequence of the -chain, are cleaved in apoptotic Jurkat T lymphocytes. Cleavage of -chain in Jurkat cells ligated by agonistic anti-Fas antibody was inhibited in the presence of peptide inhibitors of caspases, including the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone, an inhibitor of caspase-3-like activity. Fas-induced cleavage of -chain was also inhibited in Jurkat cells overexpressing the intracellular inhibitors of caspase activity, Bcl-2 or cytokine response-modifier A. In vitro translated -chain was cleaved in a similar fashion by recombinant caspase-3 or caspase-7 in a dose-dependent manner. In the presence of N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone, no cleavage of in vitro translated -chain was observed. These results suggest that the loss of TcR -chain, previously associated with tumor-induced immune dysfunction and more recently associated with tumor-induced apoptosis of T lymphocytes, is mediated by a direct degradation of the -chain by activated caspases. This is the first report of involvement of caspases in degradation of the protein.

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