TY - JOUR
T1 - Granzyme B directly and efficiently cleaves several downstream caspases substrates
T2 - Implications for CTL-induced apoptosis
AU - Andrade, Felipe
AU - Roy, Sophie
AU - Nicholson, Donald
AU - Thornberry, Nancy
AU - Rosen, Antony
AU - Casciola-Rosen, Livia
N1 - Funding Information:
This work was supported by National Institutes of Health grants AR44684 (to L. C.-R.), a Career Development Award from the Dermatology Foundation/Lever Brothers Company (to L. C.-R.), the Peggy Meyerhoff Pearlstone Foundation, the Howard Bank Memorial Fund, an Arthritis Foundation (Maryland Chapter) Institutional Grant, and the Mrs. C. Schauman Lupus Research Fund. A. R. is a Pew Scholar in the Biomedical Sciences. F. A. is supported by a Fulbright/Consejo Nacional de Ciencia y Tecnologia, Mexico Scholarship.
PY - 1998/4
Y1 - 1998/4
N2 - 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-PK(ca) 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 cleaved downstream death substrates constitutes an apoptotic effector mechanism that is insensitive to inhibitors of the signalling or execution components of the endogenous apoptotic cascade.
AB - 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-PK(ca) 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 cleaved downstream death substrates constitutes an apoptotic effector mechanism that is insensitive to inhibitors of the signalling or execution components of the endogenous apoptotic cascade.
UR - http://www.scopus.com/inward/record.url?scp=0032055097&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032055097&partnerID=8YFLogxK
U2 - 10.1016/S1074-7613(00)80550-6
DO - 10.1016/S1074-7613(00)80550-6
M3 - Article
C2 - 9586635
AN - SCOPUS:0032055097
SN - 1074-7613
VL - 8
SP - 451
EP - 460
JO - Immunity
JF - Immunity
IS - 4
ER -