Open AccessProteolytic activation of the cell death protease Yama/CPP32 by granzyme B.
Author(s) -
Long T. Quan,
Muneesh Tewari,
Karen O’Rourke,
Vishva M. Dixit,
Scott J. Snipas,
Guy G. Poirier,
Carol Ray,
David J. Pickup,
Guy S. Salvesen
Publication year - 1996
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.93.5.1972
Subject(s) - granzyme b , granzyme , proteases , proteolysis , granzyme a , serine protease , protease , microbiology and biotechnology , cytotoxic t cell , programmed cell death , deubiquitinating enzyme , chemistry , biology , apoptosis , biochemistry , perforin , enzyme , ubiquitin , in vitro , gene
The serine protease granzyme B, which is secreted by cytotoxic cells, is one of the major effectors of apoptosis in susceptible targets. To examine the apoptotic mechanism of granzyme B, we have analyzed its effect on purified proteins that are thought to be components of death pathways inherent to cells. We demonstrate that granzyme B processes interleukin 1beta-converting enzyme (ICE) and the ICE-related protease Yama (also known as CPP32 or apopain) by limited proteolysis. Processing of ICE does not lead to activation. However, processing by granzyme B leads directly to the activation of Yama, which is now able to bind inhibitors and cleave the substrate poly(ADP-ribose) polymerase whose proteolysis is a marker of apoptosis initiated by several other stimuli. Thus ICE-related proteases can be activated by serine proteases that possess the correct specificity. Activation of pro-Yama by granzyme B is within the physiologic range. Thus the cytotoxic effect of granzyme B can be explained by its activation of an endogenous protease component of a programmed cell death pathway.