Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis

Immunity. 1998 Apr;8(4):451-60. doi: 10.1016/s1074-7613(00)80550-6.

Abstract

Caspase-mediated proteolysis of downstream substrates is a critical element of the execution pathway common to all forms of apoptosis studied to date. While this caspase-dependent pathway is activated during cytotoxic lymphocyte granule-induced cell death, recent studies have also provided evidence for caspase-independent pathways. However, the mechanisms mediating these additional pathways have not been defined. The current study demonstrates that DNA-PKcs and NuMA are directly and efficiently cleaved by granzyme B in vitro and in vivo, generating unique substrate fragments not observed during other forms of apoptosis. This direct, caspase-independent ability of granzyme B to cleave downstream death substrates constitutes an apoptotic effector mechanism that is insensitive to inhibitors of the signaling or execution components of the endogenous apoptotic cascade.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, Nuclear
  • Apoptosis / immunology
  • Apoptosis / physiology*
  • Autoantigens / metabolism
  • Binding Sites / genetics
  • Caspase 3
  • Caspases*
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Cysteine Endopeptidases / metabolism*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Granzymes
  • HeLa Cells
  • Humans
  • In Vitro Techniques
  • Killer Cells, Lymphokine-Activated / immunology
  • Nuclear Matrix-Associated Proteins
  • Nuclear Proteins / metabolism
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Serine Endopeptidases / metabolism*
  • Substrate Specificity
  • T-Lymphocytes, Cytotoxic / enzymology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • fas Receptor / metabolism

Substances

  • Antigens, Nuclear
  • Autoantigens
  • DNA-Binding Proteins
  • NUMA1 protein, human
  • Nuclear Matrix-Associated Proteins
  • Nuclear Proteins
  • fas Receptor
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases