The Journal of Experimental Medicine
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Published online 20 November 2000.
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© The Rockefeller University Press, 0022-1007/2000/11/1391/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 10, November 20, 2000 1391-1402

Original Article

Granzyme B–Mediated Cytochrome C Release Is Regulated by the Bcl-2 Family Members Bid and Bax

Jeffrey A. Heibeina, Ing Swie Gopinga, Michele Barryb, Michael J. Pinkoskic, Gordon C. Shored, Douglas R. Greenc, and R. Chris Bleackleya

a Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
b Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
c Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121
d Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada
Dept. of Biochemistry, 463 Medical Sciences Bldg., University of Alberta, Edmonton, Alberta T6G 2H7, Canada.780-492-0886780-492-3968

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.

Key Words: cytotoxic T lymphocyte • granzyme B • Bcl-2 • Bid • Bax

Abbreviations used in this paper: Ad, adenovirus; DISC, death-inducing signaling complex; grB, granzyme B; HRP, horseradish peroxidase; t, truncated.

© 2000 The Rockefeller University Press


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