期刊
CELL DEATH AND DIFFERENTIATION
卷 19, 期 4, 页码 605-615出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.130
关键词
granzyme M; casp-8; FADD; proteolysis; casp cascade
资金
- National Natural Science Foundation of China [30830030, 30972676]
- 973 Programs [2010CB911902]
- CAS [XDA01010407, KSCX2-YW-R-42]
Granzyme M (GzmM), an orphan Gzm, is constitutively and abundantly expressed in innate effector natural killer cells. We previously demonstrated that GzmM induces caspase (casp)-dependent apoptosis and cytochrome c release from mitochondria. We also resolved the crystal structure for GzmM and generated its specific inhibitor. However, how GzmM causes casp activation has not been defined. Here we found that casp-8 is an initiator caspase in GzmM-induced casp cascade, which causes other casp activation and Bid cleavage. GzmM does not directly cleave procaspase-3 and Bid, whose processing is casp dependent. Casp-8 knockdown or deficient cells attenuate or abolish GzmM-induced proteolysis of procaspase-3 and Bid. Extrinsic death receptor pathway adaptor Fas-associated protein with death domain (FADD) contributes to GzmM-induced casp-8 activation. GzmM specifically cleaves FADD after Met 196 to generate truncated FADD (tFADD) that enhances its self-association for oligomerization. The oligomerized tFADD facilitates procaspase-8 recruitment to promote its auto-processing leading to casp activation cascade. FADD-deficient cells abrogate GzmM-induced activation of casp-8 and apoptosis as well as significantly inhibit lymphokine-activated killer cell-mediated cytotoxicity. FADD processing by GzmM can potentiate killing efficacy against tumor cells and intracellular pathogens. Cell Death and Differentiation (2012) 19, 605-615; doi:10.1038/cdd.2011.130; published online 7 October 2011
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