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Granulysin Induces Cathepsin B Release from Lysosomes of Target Tumor Cells to Attack Mitochondria through Processing of Bid Leading to Necroptosis¹

National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

Granulysin is a killer effector molecule localized in cytolytic granules of human NK and CTL cells. Granulysin exhibits broad antimicrobial activity and potent cytotoxic action against tumor cells. However, the molecular mechanism of granulysin-induced tumor lysis is poorly understood. In this study, we found that granulysin causes a novel cell death termed necroptosis. Granulysin can target lysosomes of target tumor cells and induce partial release of lysosomal contents into the cytosol. Relocalized lysosomal cathepsin B can process Bid to active tBid to cause cytochrome c and apoptosis-activating factor release from mitochondria. Cathepsin B silencing and Bid or Bax/Bak deficiency resists granulysin-induced cytochrome c and apoptosis-activating factor release and is less susceptible to cytolysis against target tumor cells.

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¹ This work was supported by the National Natural Science Foundation of China (Grants 30700126, 30772496, 30525005, and 30830030), 863 program (Grant 2006AA02Z4C9), 973 programs (Grants 2006CB504303 and 2006CB910901), the Innovative Program (KSCX2-YW-R-42), and the Hundred Talents Program of the Chinese Academy of Sciences.

² Address correspondence and reprint requests to Dr. Zusen Fan, National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. E-mail address: fanz{at}moon.ibp.ac.cn

³ Abbreviations used in this paper: GNLY, granulysin; cyt c, cytochrome c; Cath B, cathepsin B; MEF, mouse embryo fibroblast; STP, staurosporine; AO, acridine orange; AIF, apoptosis-inducing factor; PCD, programmed cell death; Z-RR-AMC, Z-Arg-Arg-7-amido-4-methylcoumarin hydrochloride; PI, propidium iodide; Z-FA-fmk, Z-Phe-Ala-fluormethyl ketone; WT, wild type; shRNA, short hairpin RNA; CHX, cycloheximide.