Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo

CTN Pham, TJ Ley - … of the National Academy of Sciences, 1999 - National Acad Sciences
Proceedings of the National Academy of Sciences, 1999National Acad Sciences
Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease that has been implicated in
the processing of granzymes, which are neutral serine proteases exclusively expressed in
the granules of activated cytotoxic lymphocytes. In this report, we show that cytotoxic
lymphocytes derived from DPPI−/− mice contain normal amounts of granzymes A and B, but
these molecules retain their prodipeptide domains and are inactive. Cytotoxic assays with
DPPI−/− effector cells reveal severe defects in the induction of target cell apoptosis (as …
Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease that has been implicated in the processing of granzymes, which are neutral serine proteases exclusively expressed in the granules of activated cytotoxic lymphocytes. In this report, we show that cytotoxic lymphocytes derived from DPPI−/− mice contain normal amounts of granzymes A and B, but these molecules retain their prodipeptide domains and are inactive. Cytotoxic assays with DPPI−/− effector cells reveal severe defects in the induction of target cell apoptosis (as measured by [125I]UdR release) at both early and late time points; this defect is comparable to that detected in perforin−/− or granzyme A−/− × B−/− cytotoxic lymphocytes. DPPI therefore plays an essential role in the in vivo processing and activation of granzymes A and B, which are required for cytotoxic lymphocyte granule-mediated apoptosis.
National Acad Sciences