Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis.
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.
Andrade
F
F
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Roy
S
S
Nicholson
D
D
Thornberry
N
N
Rosen
A
A
Casciola-Rosen
L
L
D034961:Antigens, Nuclear; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D001324:Autoantigens / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D053148:Caspase 3; D020169:Caspases; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D053804:Granzymes; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
D034961:Antigens, Nuclear; D001324:Autoantigens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins; D019014:fas Receptor; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases