TY - JOUR
T1 - Cytotoxic cell granule-mediated apoptosis
T2 - Perforin delivers granzyme b-serglycin complexes into target cells without plasma membrane pore formation
AU - Metkar, Sunil S.
AU - Wang, Baikun
AU - Aguilar-Santelises, Miguel
AU - Raja, Srikumar M.
AU - Uhlin-Hansen, Lars
AU - Podack, Eckhard
AU - Trapani, Joseph A.
AU - Froelich, Christopher J.
N1 - Funding Information:
This work is dedicated to Arnold Greenberg for his seminal observations in granule-mediated apoptosis. We thank Guy Salvesen and Henning Stennicke (Burnham Institute, CA) for recombinant procaspases and Jonathan Moore and Lawrence Kwong for technical assistance. This work was supported by NIH AI/GM 44941 in addition to National and Chicago Chapter Arthritis Foundation Biomedical Grants (C.J.F.) and NIH CA 39201, 7904, 80228, and DOD DAMDS 12-98-1-8317 (E.R.P.). J.A.T. is supported by NHMRC of Australia.
PY - 2002
Y1 - 2002
N2 - The mechanism underlying perforin (PFN)-dependent delivery of apoptotic granzymes during cytotoxic cell granule-mediated death remains speculative. Granzyme B (GrB) and perforin were found to coexist as multimeric complexes with the proteoglycan serglycin (SG) in cytotoxic granules, and cytotoxic cells were observed to secrete exclusively macromolecular GrB-SG. Contrary to the view that PFN acts as a gateway for granzymes through the plasma membrane, monomeric PFN and, strikingly, PFN-SG complexes were shown to mediate cytosolic delivery of macromolecular GrB-SG without producing detectable plasma membrane pores. These results indicate that granule-mediated apoptosis represents a phenomenon whereby the target cell perceives granule contents as a multi meric complex consisting of SG, PFN, and granzymes, which are, respectively, the scaffold, translocator, and targeting/informational components of this modular delivery system.
AB - The mechanism underlying perforin (PFN)-dependent delivery of apoptotic granzymes during cytotoxic cell granule-mediated death remains speculative. Granzyme B (GrB) and perforin were found to coexist as multimeric complexes with the proteoglycan serglycin (SG) in cytotoxic granules, and cytotoxic cells were observed to secrete exclusively macromolecular GrB-SG. Contrary to the view that PFN acts as a gateway for granzymes through the plasma membrane, monomeric PFN and, strikingly, PFN-SG complexes were shown to mediate cytosolic delivery of macromolecular GrB-SG without producing detectable plasma membrane pores. These results indicate that granule-mediated apoptosis represents a phenomenon whereby the target cell perceives granule contents as a multi meric complex consisting of SG, PFN, and granzymes, which are, respectively, the scaffold, translocator, and targeting/informational components of this modular delivery system.
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U2 - 10.1016/S1074-7613(02)00286-8
DO - 10.1016/S1074-7613(02)00286-8
M3 - Article
C2 - 11911826
AN - SCOPUS:0036195424
VL - 16
SP - 417
EP - 428
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 3
ER -
