Section 12
Chapter 11,338

Selective inhibition of dipeptidyl peptidase I, not caspases, prevents the partial processing of procaspase-3 in CD3-activated human CD8 (+) T lymphocytes

Bidère, N.; Briet, M.; Dürrbach, A.; Dumont, Céline.; Feldmann, Jérôme.; Charpentier, B.; de Saint-Basile, Gève.; Senik, A.

Journal of Biological Chemistry 277(35): 32339-32347


ISSN/ISBN: 0021-9258
PMID: 12080079
DOI: 10.1074/jbc.m205153200
Accession: 011337055

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Activation of primary human T cells by anti-CD3 and interleukin-2 resulted in partial processing of procaspase-3 in activated nonapoptotic (Delta Psi(m)high) CD8(+) T cells but not in CD4(+) T cells. Apical caspases-8 and -9 were not activated, and Bid was not processed to truncated Bid. Boc-D.fmk, a broad spectrum caspase inhibitor, did not prevent this process, whereas GF.dmk, a selective inhibitor of dipeptidyl peptidase I, was effective. Dipeptidyl peptidase I is required for the activation of granule-associated serine proteases. It is enriched in the cytolytic granules of cytotoxic lymphocytes, where it promotes the proteolytic activation of progranzymes A and B. Inhibition of granzyme B (GrB)-like serine proteases by Z-AAD.cmk prevented partial processing of procapase-3, whereas inhibition of GrA activity by D-FPR.cmk had no effect. Specific inhibitors of other lysosomal proteases such as cathepsins B, L, and D did not interfere in this event. Patients with Chediak-Higashi syndrome or with perforin deficiency also displayed partial processing of procaspase-3, excluding the involvement of granule exocytosis for the delivery of the serine protease in cause. The p20/p12 processing pattern of procaspase-3 in our model points to GrB, the sole serine protease with caspase activity. Small amounts of GrB were indeed exported from cytolytic granules to the cytosol of a significant fraction of GrB-positive cells.

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