Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3

Arul M. Chinnaiyan, William L. Hanna, Kim Orth, Hangjun Duan, Guy G. Poirier, Christopher J. Froelich, Vishva M. Dixit

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells provide immune surveillance against viruses and neoplasms, and play a central role in the pathogenesis of autoimmune disease, AIDS and graft rejection [1,2]. Thus, it is important to understand the precise molecular mechanism(s) whereby cytotoxic lymphocytes destroy susceptible target cells. Granule- mediated cytotoxicity requires a combination of both perforin and granzyme B [3]. Perforin polymerizes to form transmembrane channels and presumably allows granzyme B access to target cell substrates, which until recently, were unknown. One clue to the identity of the physiological substrate(s) activated by granzyme B comes from its unusual specificity for denying synthetic substrates after aspartate residues [4]. Members of the ICE/CED-3 family of cysteine proteases are prime candidates as they are important apoptotic effectors [5,6] and are expressed as zymogens, which can be processed to form active heterodimeric enzymes after cleavage at specific aspartate residues. Previous studies have shown that granzyme B proteolytically activates the cell death effector Yama/CPP32/apopain [7,8] (referred to hera is Yama). Here we report that granzyme B also activates ICE-LAP3/Mch3/CMH-1 (referred to here as ICE-LAP3), which, along with Yama and MCh2, forms a subset of the ICE/CED-3 family of cysteine proteases most closely related to the Caenorhabditis elegans cell death gene, CED-3 [6,9]. Importantly, Jurkat T cells incubated with granzyme B end u sublyric concentration of perforin undergo apoptosis, which is preceded by the activation of endogenous ICE-LAP3. Thus, we propose that granzyme B mediates apoptosis by directly engaging the target cell's death effector machinery, which is probably composed of an arsenal of intracellular, CED-3-like cysteine proteases.

Original languageEnglish (US)
Pages (from-to)897-899
Number of pages3
JournalCurrent Biology
Volume6
Issue number7
DOIs
StatePublished - Jan 1 1996

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Chinnaiyan, A. M., Hanna, W. L., Orth, K., Duan, H., Poirier, G. G., Froelich, C. J., & Dixit, V. M. (1996). Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3. Current Biology, 6(7), 897-899. https://doi.org/10.1016/S0960-9822(02)00614-0