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PMID: 11085742 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax.

The Journal of experimental medicine ·Vol. 192 ·No. 10 ·2000-11-20 ·Pages 1391-402

Heibein JA, Goping IS, Barry M, Pinkoski MJ, Shore GC, Green DR, Bleackley RC

Abstract

Cytotoxic T lymphocytes (CTLs) destroy target cells through a mechanism involving the exocytosis of cytolytic granule components including granzyme B (grB) and perforin, which have been shown to induce apoptosis through caspase activation. However, grB has also been linked with caspase-independent disruption of mitochondrial function. We show here that cytochrome c release requires the direct proteolytic cleavage of Bid by grB to generate a 14-kD grB-truncated product (gtBid) that translocates to mitochondria. In turn, gtBid recruits Bax to mitochondria through a caspase-independent mechanism where it becomes integrated into the membrane and induces cytochrome c release. Our results provide evidence for a new pathway by which CTLs inflict damage and explain the caspase-independent mechanism of mitochondrial dysfunction.

MeSH Terms
BH3 Interacting Domain Death Agonist Protein Carrier Proteins/metabolism Cell Death Cytochrome c Group/metabolism Cytosol/metabolism Cytotoxicity, Immunologic Granzymes Humans Intracellular Membranes/metabolism Jurkat Cells/virology Mitochondria/metabolism Models, Biological Protein Processing, Post-Translational Protein Transport Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-bcl-2/metabolism Serine Endopeptidases/metabolism T-Lymphocytes, Cytotoxic/metabolism Tumor Cells, Cultured bcl-2-Associated X Protein
Chemicals
BAX protein, human BH3 Interacting Domain Death Agonist Protein BID protein, human Carrier Proteins Cytochrome c Group Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 bcl-2-Associated X Protein GZMB protein, human Granzymes Serine Endopeptidases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Heibein J A
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Goping I S
Barry M
Pinkoski M J
Shore G C
Green D R
Bleackley R C
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.192.10.1391
Published
2000-11-20
Pages
1391-402
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193181
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.192.10.1391 PMC Full Text View journal details
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