Granule-mediated killing: Pathways for granzyme B-initiated apoptosis

Robert V. Talanian, Xiao He Yang, Jane Turbov, Prem Seth, Tariq Ghayur, Carlos A. Casiano, Kim Orth, Christopher J. Froelich

Research output: Contribution to journalArticle

153 Scopus citations

Abstract

We report that the serine protease granzyme B (GrB), which is crucial for granule-mediated cell killing, initiates apoptosis in target cells by first maturing caspase-10. In addition, GrB has a limited capacity to mature other caspases and to cause cell death independently of the caspases. Compared with other members, GrB in vitro most efficiently processes caspase- 7 and -10. In a human cell model, full maturation of caspase-7 does not occur unless caspase-10 is present. Furthermore, GrB matured caspase-3 with less efficiency than caspase-7 or caspase-10. With the caspases fully inactivated by peptidic inhibitors, GrB induced in Jurkat cells growth arrest and, over a delayed time period, cell death. Thus, the primary mechanism by which GrB initiates cell death is activation of the caspases through caspase-10. However, under circumstances where caspase-10 is absent or dysfunctional, GrB can act through secondary mechanisms including activation of other caspases and direct cell killing by cleavage of noncaspase substrates. The redundant functions of GrB ensure the effectiveness of granule-mediated cell killing, even in target cells that lack the expression or function (e.g., by mutation or a viral serpin) of one or more of the caspases, providing the host with overlapping safeguards against aberrantly replicating, nonself or virally infected cells.

Original languageEnglish (US)
Pages (from-to)1323-1331
Number of pages9
JournalJournal of Experimental Medicine
Volume186
Issue number8
DOIs
StatePublished - Oct 20 1997

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Talanian, R. V., Yang, X. H., Turbov, J., Seth, P., Ghayur, T., Casiano, C. A., Orth, K., & Froelich, C. J. (1997). Granule-mediated killing: Pathways for granzyme B-initiated apoptosis. Journal of Experimental Medicine, 186(8), 1323-1331. https://doi.org/10.1084/jem.186.8.1323