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

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 [(125)I]UdR release) at both early and late time points; this defect is comparable to that detected in perforin-/- or granzyme A-/- x 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.

Pubmed ID: 10411926

Authors

  • Pham CT
  • Ley TJ

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 20, 1999

Associated Grants

  • Agency: NCI NIH HHS, Id: CA49712
  • Agency: NIDDK NIH HHS, Id: DK49786
  • Agency: NHLBI NIH HHS, Id: K08-HL-03774

Mesh Terms

  • Animals
  • Apoptosis
  • Cathepsin C
  • Cytoplasmic Granules
  • Cytotoxicity Tests, Immunologic
  • Deoxyuridine
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • Enzyme Activation
  • Flow Cytometry
  • Gene Targeting
  • Granzymes
  • Killer Cells, Lymphokine-Activated
  • Membrane Glycoproteins
  • Mice
  • Mice, Knockout
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Protein Precursors
  • Serine Endopeptidases
  • T-Lymphocytes, Cytotoxic