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Granzyme B delivered via adenovirus (AD) requires caspase 3 in order to kill cells.

When a cytotoxic lymphocyte delivers granzyme B to a target cell, current models emphasize that the enzyme induces apoptosis through a mitochondria-centered pathway, cleaving the proapoptotic Bcl-2 family member Bid to cause mitochondrial permeabilization. On page 875, Metkar et al. overturn this view, showing that in the dominant pathway granzyme B begins by processing procaspase-3, whereas mitochondria are secondary components that amplify the signal once caspase-3 has been activated. The work adds to recent evidence that caspases can initiate apoptosis, whereas mitochondria serve as signal amplifiers.

The authors used a variety of strategies to avoid common pitfalls during granzyme- mediated apoptosis assays. In past assays, uncomplexed granzyme B was added to cell extracts. Granzyme B in the new assays was delivered into cells using adenovirus particles, and was presented in a complex with the proteoglycan serglycin to mimic the enzyme's natural state. Doing the apoptosis assays with whole cells minimized the risk of proteolysis occurring at sites not normally frequented by granzyme B.

In this system, Bid cleavage was not detected, and cells deficient in procaspase-3 failed to undergo mitochondrial depolarization or DNA fragmentation, indicating that granzyme B acts first through procaspase-3 rather than the mitochondria. Caspase-3–induced permeabilization of the mitochondria amplifies the death signal but, based on assays with cells harboring a Bax/Bak deletion, this amplification is not essential for apoptosis.

Alan W. Dove

alanwdove{at}earthlink.net

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Related Article

Granzyme B activates procaspase-3 which signals a mitochondrial amplification loop for maximal apoptosis

Sunil S. Metkar, Baikun Wang, Michelle L. Ebbs, Jin H. Kim, Yong J. Lee, Srikumar M. Raja, and Christopher J. Froelich
J. Cell Biol. 2003 160: 875-885. [Abstract] [Full Text] [PDF]

This Article PDF (Full Text) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dove, A. W. Search for Related Content PubMed Articles by Dove, A. W. Related Collections Related Article Social Bookmarking                      What's this?