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Bid Leading to Necroptosis Attack Mitochondria Through Processing Of Granulysin Induces Cathepsin B Release from Lysosomes of Target Tumor Cells to Attack Mitochondria through Processing of Bid Leading to Necroptosis This information is current as of September 24, 2021. Honglian Zhang, Chao Zhong, Lei Shi, Yuming Guo and Zusen Fan J Immunol 2009; 182:6993-7000; ; doi: 10.4049/jimmunol.0802502 http://www.jimmunol.org/content/182/11/6993 Downloaded from References This article cites 40 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/182/11/6993.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Granulysin Induces Cathepsin B Release from Lysosomes of Target Tumor Cells to Attack Mitochondria through Processing of Bid Leading to Necroptosis1 Honglian Zhang, Chao Zhong, Lei Shi, Yuming Guo, and Zusen Fan2 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 Downloaded from release and is less susceptible to cytolysis against target tumor cells. The Journal of Immunology, 2009, 182: 6993–7000. ranule exocytosis-mediated cytolysis plays a major role in GNLY even at a very high concentration. Krensky and colleagues the innate and adaptive immunity against intracellular (18) generated GNLY-transgenic mice and exhibited their signif- G pathogens and tumor cells. Granulysin (GNLY)3 is colo- icant protection against lethal tumor challenge. However, the mo- calized in the cytotoxic granules along with a pore-forming protein, lecular mechanism of GNLY-induced tumor lysis is less defined. perforin (1, 2). GNLY has two major forms, 15 and 9 kDa. The 9-kDa Lysosomes have been considered to be solely involved in ne- http://www.jimmunol.org/ form is processed from the larger precursor 15-kDa form and only the crotic and autophagic cell death for many years. Likewise, lyso- 9-kDa GNLY exerts cytolytic activity (3). GNLY is a member of the somal proteases were believed to be limited to nonspecific intra- saposin-like protein family of lipid-binding proteins that includes cellular protein degradation in the lysosome. However, recent amoebapores, saposins, and NK lysin (4–6). GNLY exhibits broad- accumulating evidence strongly demonstrated that lysosomes par- spectrum antimicrobial activity against both Gram-positive and -neg- ticipate in the induction of apoptosis beyond that of simple “gar- ative bacteria, fungi, and parasites (7–9). Recent reports showed that bage disposals.” A complete destruction of lysosomes with release cytotoxic CD8ϩ T cells and CD4ϩ T cells use GNLY, rather than of high concentrations of lysosomal enzymes into the cytosol re- perforin, to kill Cryptococcus neoformans (10, 11). sults in unregulated necrosis, whereas partial, sequential perme- by guest on September 24, 2021 Besides its antimicrobial function, GNLY also harbors potent abilization triggers programmed cell death (PCD) (19). Several cytotoxic activity against tumor cells (12). GNLY can lyse Jurkat lysosomal proteases known as cathepsins, were released into the cells with apoptotic features in vitro. This apoptosis is associated cytosol of target cells as a result of moderate lysosomal disruption with an increase of intracellular calcium and a decrease of intra- (20, 21). Cathepsin B (Cath B) from lysosomes enhances mitochon- cellular potassium. Increasing intracellular calcium causes mito- drial release of cyt c and subsequent caspase activation in TNF-treated chondrial damage to release cytochrome c (cyt c) and apoptosis- hepatocytes (22). Cathepsin D triggers Bax activation resulting in se- inducing factor (AIF) leading to mitochondria-dependent cell lective AIF release in T lymphocytes in the early commitment phase death (13–17). Mitochondria-deficient RBC were not lysed by to apoptosis. An important cytosolic factor, Bid, was reported to be cleaved by some cathepsins and translocated to the mitochondria fol- lowing lysosomal disruption by lysosomotropic agents (23). Thus, a National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China lysosomal pathway is connected with a mitochondrial pathway to ini- tiate apoptosis through these Bcl-2 family proteins. In this study, we Received for publication July 30, 2008. Accepted for publication March 20, 2009. found that GNLY can target lysosomes of target tumor cells and in- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance duce partial release of lysosomal contents. Relocalized lysosomal with 18 U.S.C. Section 1734 solely to indicate this fact. Cath B can process Bid to active tBid to cause cyt c and AIF release 1 This work was supported by the National Natural Science Foundation of China from mitochondria. Bid or Bak/Bax deficiency resists GNLY-induced (Grants 30700126, 30772496, 30525005, and 30830030), 863 program (Grant cyt c and AIF release and necroptosis. 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. Materials and Methods 2 Address correspondence and reprint requests to Dr. Zusen Fan, National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophys- Cell lines, Abs, and reagents ics, Chinese Academy of Sciences, Beijing 100101, China. E-mail address: fanz@ moon.ibp.ac.cn Jurkat cells were grown in RPMI 1640 and HeLa cells in DMEM supple- mented with 10% FCS, 50 ␮M 2-ME, 100 U/ml penicillin, and 100 ␮g/ml 3 Abbreviations used in this paper: GNLY, granulysin; cyt c, cytochrome c; Cath B, streptomycin. Mouse embryo fibroblasts (MEFs) were cultured in DMEM cathepsin B; MEF, mouse embryo fibroblast; STP, staurosporine; AO, acridine or- supplemented with 10% FCS, 100 ␮M asparagine, and 50 ␮M 2-ME. Bid ange; AIF, apoptosis-inducing factor; PCD, programmed cell death; Z-RR-AMC, Z-Arg-Arg-7-amido-4-methylcoumarin hydrochloride; PI, propidium iodide; Z-FA- wild-type (WT) MEFs and Bid knockout MEFs were provided by Dr. A. fmk, Z-Phe-Ala-fluormethyl ketone; WT, wild type; shRNA, short hairpin RNA; Strasser (The Walter and Eliza Hall Institute of Medical Research, CHX, cycloheximide. Parkville, Australia) and Bax/Bak double knockout MEFs were provided by Dr. Q. Chen (Institute of Zoology, Chinese Academy of Sciences, Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 Beijing, China). Human PBMC and RBC were obtained from healthy www.jimmunol.org/cgi/doi/10.4049/jimmunol.0802502 6994 GNLY-INDUCED NECROPTOSIS BY TARGETING LYSOSOMES volunteers and isolated by a lymphocyte separation kit. Commercial Abs were goat polyclonal to Cath B (Santa Cruz Biotechnology) for confocal and mouse anti-Cath B (Millipore) for Western blotting, rabbit polyclonal to LAMP-1 (Abcam), mouse anti-cyt c (BD Pharmingen), rabbit anti-AIF (BD Pharmingen), monoclonal anti-␤-actin (Sigma-Aldrich), HRP-conju- gated sheep anti-mouse IgG and HRP-conjugated sheep anti-rabbit IgG (Santa Cruz Biotechnology), Alexa Fluor 488-conjugated donkey anti- mouse IgG (Molecular Probes), and Alexa Fluor 594-conjugated donkey anti-rabbit IgG (Molecular Probes). Rabbit antiserum against Bid was pro- vided by Dr. X. Wang (University of Texas Southwestern Medical Center, Dallas, TX) and mouse anti-GNLY was provided by Dr. A. Krensky (Stan- ford University, Stanford, CA). Propidium iodide (PI), acridine orange (AO), and Z-Arg-Arg-7-amido-4-methylcoumarin hydrochloride were ob- tained from Sigma-Aldrich. Mitotracker was from Molecular Probes. Z- FA-fmk and FITC-annexin V were purchased from BD Pharmingen. Expression and purification of recombinant GNLY pET28a-GNLY (a gift from A. Krensky) was expressed in Escherichia coli BL21-AI and the soluble supernatant was purified on a nickel column. Then the His tag was removed by thrombin treatment. Reverse-phase HPLC was used to further purification. After lyophilization, the protein
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