Human NK cell lytic granules and regulation of their exocytosis

Frontiers in Immunology

Volumn 3, Issue NOV, 2012, Pages

  Krzewski, Konrad ^a   Coligan, John E ^a  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

Cytotoxic lymphocytes; Cytotoxicity; Exocytosis; Lysosomes; Lytic granules; NK cells

Indexed keywords

EID: 84874218764     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2012.00335     Document Type: Review

References (220)

1. Adrain, C., Murphy, B. M., and Martin, S. J. (2005). Molecular ordering of the caspase activation cascade initiated by the cytotoxic T lymphocyte/natural killer (CTL/NK) protease granzyme B. J. Biol. Chem. 280, 4663-4673.
2. Agerberth, B., Charo, J., Werr, J., Olsson, B., Idali, F., Lindbom, L., et al. (2000). The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96, 3086-3093.
3. Aktas, E., Kucuksezer, U. C., Bilgic, S., Erten, G., andDeniz, G. (2009). Relationship between CD107a expression and cytotoxic activity. Cell. Immunol. 254, 149-154.
4. Almeida, C. R., Ashkenazi, A., Shahaf, G., Kaplan, D., Davis, D.M., and Mehr, R. (2011). Human NK cells differ more in their KIR2DL1-dependent thresholds for HLA-Cw6-mediated inhibition than in their maximal killing capacity. PLoS ONE 6:e24927. doi: 10.1371/journal.pone.0024927
5. Almeida, C. R., and Davis, D. M. (2006). Segregation of HLA-C from ICAM-1 at NK cell immune synapses is controlled by its cell surface density. J. Immunol. 177, 6904-6910.
6. Alter, G., Malenfant, J. M., and Altfeld, M. (2004). CD107a as a functional marker for the identification of natural killer cell activity. J. Immunol. Methods 294, 15-22.
7. Anderson, D.H., Sawaya, M.R., Cascio, D., Ernst, W., Modlin, R., Krensky, A., et al. (2003). Granulysin crystal structure and a structure-derived lytic mechanism. J. Mol. Biol. 325, 355-365.
8. Andrade, F., Fellows, E., Jenne, D. E., Rosen, A., and Young, C. S. (2007). Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition. EMBO J. 26, 2148-2157.
9. Andzelm, M. M., Chen, X., Krzewski, K., Orange, J. S., and Strominger, J. L. (2007). Myosin IIA is required for cytolytic granule exocytosis in human NK cells. J. Exp. Med. 204, 2285-2291.
10. Arneson, L. N., Brickshawana, A., Segovis, C. M., Schoon, R. A., Dick, C. J., and Leibson, P. J. (2007). Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J. Immunol. 179, 3397-3401.
11. Banerjee, P. P., Pandey, R., Zheng, R., Suhoski, M. M., Monaco-Shawver, L., and Orange, J. S. (2007). Cdc42interacting protein-4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse. J. Exp. Med. 204, 2305-2320.
12. Barber, D. F., Faure, M., and Long, E. O. (2004). LFA-1 contributes an early signal for NK cell cytotoxicity. J. Immunol. 173, 3653-3659.
13. Barry, M., Heibein, J. A., Pinkoski, M. J., Lee, S. F., Moyer, R. W., Green, D. R., et al. (2000). Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. Mol. Cell. Biol. 20, 3781-3794.
14. Beresford, P. J., Zhang, D., Oh, D. Y., Fan, Z., Greer, E.L., Russo, M. L., et al. (2001). Granzyme A activates an endoplasmic reticulumassociated caspase-independent nuclease to induce single-stranded DNA nicks. J. Biol. Chem. 276, 43285-43293.
15. Bhat, R., and Watzl, C. (2007). Serial killing of tumor cells by human natural killer cells-enhancement by therapeutic antibodies. PLoS ONE 2:e326. doi: 10.1371/journal.pone.0000326
16. Blott, E. J., Bossi, G., Clark, R., Zvelebil, M., and Griffiths, G. M. (2001). Fas ligand is targeted to secretory lysosomes via a proline-rich domain in its cytoplasmic tail. J. Cell. Sci. 114, 2405-2416.
17. Blott, E. J., and Griffiths, G. M. (2002). Secretory lysosomes. Nat. Rev. Mol. Cell Biol. 3, 122-131.
18. Bossi, G., and Griffiths, G. M. (1999). Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells. Nat. Med. 5, 90-96.
19. Bovenschen, N., De Koning, P. J., Quadir, R., Broekhuizen, R., Damen, J. M., Froelich, C. J., et al. (2008). NK cell protease granzyme M targets alpha-tubulin and disorganizes the microtubule network. J. Immunol. 180, 8184-8191.
20. Brennan, A. J., Chia, J., Browne, K. A., Ciccone, A., Ellis, S., Lopez, J. A., et al. (2011). Protection from endogenous perforin: glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes. Immunity 34, 879-892.
21. Brown, A. C., Dobbie, I. M., Alakoskela, J.M., Davis, I., andDavis, D. M. (2012). Super-resolution imaging of remodelled synaptic actin reveals different synergies between NK cell receptors and integrins. Blood. doi: 10.1182/blood-2012-05429977. [Epub ahead of print].
22. Brown, A. C., Oddos, S., Dobbie, I. M., Alakoskela, J. M., Parton, R. M., Eissmann, P., et al. (2011). Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy. PLoS Biol. 9:e1001152. doi: 10.1371/journal.pbio.1001152
23. Bryceson, Y. T., Ljunggren, H. G., and Long, E. O. (2009). Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114, 2657-2666.
24. Bryceson, Y.T., March, M.E., Barber, D.F., Ljunggren, H.-G., andLong, E. O. (2005). Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J. Exp. Med. 202, 1001-1012.
25. Bryceson, Y. T., March, M. E., Ljunggren, H.-G., and Long, E. O. (2006). Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev. 214, 73-91.
26. Bryceson, Y. T., March, M. E., Ljunggren, H.-G., and Long, E. O. (2006b). Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107, 159-166.
27. Bryceson, Y. T., Pende, D., Maul Pavicic, A., Gilmour, K.C., Ufheil, H., Vraetz, T., et al. (2012). A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 119, 2754-2763.
28. Bryceson, Y. T., Rudd, E., Zheng, C., Edner, J., Ma, D., Wood, S. M., et al. (2007). Defective cytotoxic lymphocyte degranulation in syntaxin11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood 110, 1906-1915.
29. Burkhardt, J. K., Hester, S., and Argon, Y. (1989). Two proteins targeted to the same lytic granule compartment undergo very different posttranslational processing. Proc. Natl. Acad. Sci. U.S.A. 86, 7128-7132.
30. Burkhardt, J. K., Hester, S., Lapham, C. K., and Argon, Y. (1990). The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments. J. Cell Biol. 111, 2327-2340.
31. Butler, B., and Cooper, J. A. (2009). Distinct roles for the actin nucleators Arp2/3 and hdia1 during NKmediated cytotoxicity. Curr. Biol. 19, 1886-1896.
32. Butler, B., Kastendieck, D. H., and Cooper, J. A. (2008). Differently phosphorylated forms of the cortactin homolog HS1 mediate distinct functions in natural killer cells. Nat. Immunol. 9, 887-897.
33. Casciola-Rosen, L., Andrade, F., Ulanet, D., Wong, W.B., andRosen, A. (1999). Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity. J. Exp. Med. 190, 815-826.
34. Casey, T. M., Meade, J. L., and Hewitt, E. W. (2007). Organelle proteomics: identification of the exocytic machinery associated with the natural killer cell secretory lysosome. Mol. Cell. Proteomics 6, 767-780.
35. Chalifour, A., Jeannin, P., Gauchat, J.F., Blaecke, A., Malissard, M., N'Guyen, T., et al. (2004). Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production. Blood 104, 1778-1783.
36. Chen, X., Allan, D.S., Krzewski, K., Ge, B., Kopcow, H., andStrominger, J. L. (2006). CD28-stimulated ERK2 phosphorylation is required for polarization of the microtubule organizing center and granules in YTS NK cells. Proc. Natl. Acad. Sci. U.S.A. 103, 10346-10351.
37. Chen, X., Trivedi, P. P., Ge, B., Krzewski, K., and Strominger, J. L. (2007). Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 104, 6329-6334.
38. Chia, J., Thia, K., Brennan, A. J., Little, M., Williams, B., Lopez, J. A., et al. (2012). Fatal immune dysregulation due to a gain of glycosylation mutation in lymphocyte perforin. Blood 119, 1713-1716.
39. Chiesa, S., Tomasello, E., Vivier, E., and Vély, F. (2005). Coordination of activating and inhibitory signals in natural killer cells. Mol. Immunol. 42, 477-484.
40. Chiu, T. T., Patel, N., Shaw, A. E., Bamburg, J. R., and Klip, A. (2010). Arp2/3and cofilin-coordinated actin dynamics is required for insulin-mediated GLUT4 translocation to the surface of muscle cells. Mol. Biol. Cell 21, 3529-3539.
41. Chowdhury, D., Beresford, P.J., Zhu, P., Zhang, D., Sung, J. S., Demple, B., et al. (2006). The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme Amediated cell death. Mol. Cell 23, 133-142.
42. Clayberger, C., Finn, M. W., Wang, T., Saini, R., Wilson, C., Barr, V. A., et al. (2012). 15 kDa granulysin causes differentiation of monocytes to dendritic cells but lacks cytotoxic activity. J. Immunol. 188, 6119-6126.
43. Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., et al. (2006). Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function. Blood 108, 3079-3084.
44. Cooper, M. A., Fehniger, T. A., Fuchs, A., Colonna, M., and Caligiuri, M. A. (2004). NK cell and DC interactions. Trends Immunol. 25, 47-52.
45. Cote, M., Menager, M. M., Burgess, A., Mahlaoui, N., Picard, C., Schaffner, C., et al. (2009). Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J. Clin. Invest. 119, 3765-3773.
46. Cullen, S. P., Afonina, I. S., Donadini, R., Luthi, A.U., Medema, J.P., Bird, P. I., et al. (2009). Nucleophosmin is cleaved and inactivated by the cytotoxic granule protease granzyme M during natural killer cell-mediated killing. J. Biol. Chem. 284, 5137-5147.
47. D'Angelo, M. E., Bird, P. I., Peters, C., Reinheckel, T., Trapani, J. A., and Sutton, V. R. (2010). Cathepsin H is an additional convertase of progranzyme B. J. Biol. Chem. 285, 20514-20519.
48. Davis, D. M. (2002). Assembly of the immunological synapse for T cells and NK cells. Trends Immunol. 23, 356-363.
49. Della Chiesa, M., Vitale, M., Carlomagno, S., Ferlazzo, G., Moretta, L., and Moretta, A. (2003). The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors. Eur. J. Immunol. 33, 1657-1666.
50. Deng, A., Chen, S., Li, Q., Lyu, S. C., Clayberger, C., and Krensky, A. M. (2005). Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator. J. Immunol. 174, 5243-5248.
51. Dourmashkin, R. R., Deteix, P., Simone, C.B., andHenkart, P. (1980). Electron microscopic demonstration of lesions in target cell membranes associated with antibody-dependent cellular cytotoxicity. Clin. Exp. Immunol. 42, 554-560.
52. Edwards, K.M., Kam, C.M., Powers, J. C., and Trapani, J. A. (1999). The human cytotoxic T cell granule serine protease granzyme H has chymotrypsin-like (chymase) activity and is taken up into cytoplasmic vesicles reminiscent of granzyme B-containing endosomes. J. Biol. Chem. 274, 30468-30473.
53. Elstak, E. D., Neeft, M., Nehme, N. T., Voortman, J., Cheung, M., Goodarzifard, M., et al. (2011). The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane. Blood 118, 1570-1578.
54. Endt, J., McCann, F. E., Almeida, C. R., Urlaub, D., Leung, R., Pende, D., et al. (2007). Inhibitory receptor signals suppress ligation-induced recruitment of NKG2D to GM1rich membrane domains at the human NK cell immune synapse. J. Immunol. 178, 5606-5611.
55. Falschlehner, C., Emmerich, C. H., Gerlach, B., and Walczak, H. (2007). TRAIL signalling: decisions between life and death. Int. J. Biochem. Cell Biol. 39, 1462-1475.
56. Fan, Z., Beresford, P. J., Zhang, D., and Lieberman, J. (2002). HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Mol. Cell. Biol. 22, 2810-2820.
57. Fan, Z., Beresford, P.J., Oh, D.Y., Zhang, D., and Lieberman, J. (2003). Tumor suppressor NM23H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 112, 659-672.
58. Fan, Z., Beresford, P. J., Zhang, D., Xu, Z., Novina, C. D., Yoshida, A., et al. (2003). Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat. Immunol. 4, 145-153.
59. Fauriat, C., Long, E. O., Ljunggren, H. G., and Bryceson, Y. T. (2010). Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood 115, 2167-2176.
60. Fellows, E., Gil-Parrado, S., Jenne, D. E., and Kurschus, F. C. (2007). Natural killer cell-derived human granzyme H induces an alternative, caspase-independent cell-death program. Blood 110, 544-552.
61. Ferlazzo, G., Tsang, M. L., Moretta, L., Melioli, G., Steinman, R. M., and Munz, C. (2002). Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J. Exp. Med. 195, 343-351.
62. Fernandez, N. C., Lozier, A., Flament, C., Ricciardi-Castagnoli, P., Bellet, D., Suter, M., et al. (1999). Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat. Med. 5, 405-411.
63. Feske, S. (2010). CRAC channelopathies. Pflugers Arch. 460, 417-435.
64. Franco, S. J., Rodgers, M. A., Perrin, B. J., Han, J., Bennin, D. A., Critchley, D. R., et al. (2004). Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat. Cell Biol. 6, 977-983.
65. Fraser, S. A., Karimi, R., Michalak, M., and Hudig, D. (2000). Perforin lytic activity is controlled by calreticulin. J. Immunol. 164, 4150-4155.
66. Froelich, C.J., Hanna, W.L., Poirier, G. G., Duriez, P. J., D'Amours, D., Salvesen, G. S., et al. (1996). Granzyme B/perforin-mediated apoptosis of Jurkat cells results in cleavage of poly(ADP-ribose) polymerase to the 89-kDa apoptotic fragment and less abundant 64-kDa fragment. Biochem. Biophys. Res. Commun. 227, 658-665.
67. Froelich, C. J., Orth, K., Turbov, J., Seth, P., Gottlieb, R., Babior, B., et al. (1996). New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis. J. Biol. Chem. 271, 29073-29079.
68. Fujita-Yoshigaki, J., Katsumata, O., Matsuki, M., Yoshigaki, T., Furuyama, S., and Sugiya, H. (2006). Difference in distribution of membrane proteins between lowand high-density secretory granules in parotid acinar cells. Biochem. Biophys. Res. Commun. 344, 283-292.
69. Galandrini, R., Micucci, F., Tassi, I., Cifone, M.G., Cinque, B., Piccoli, M., et al. (2005). Arf6, a new player in FcgammaRIIIA lymphocytemediated cytotoxicity. Blood 106, 577-583.
70. Gerosa, F., Baldani-Guerra, B., Nisii, C., Marchesini, V., Carra, G., and Trinchieri, G. (2002). Reciprocal activating interaction between natural killer cells and dendritic cells. J. Exp. Med. 195, 327-333.
71. Ghosh, D., Lippert, D., Krokhin, O., Cortens, J. P., and Wilkins, J. A. (2010). Defining the membrane proteome of NK cells. J. Mass Spectrom. 45, 1-25.
72. Glickman, J. N., and Kornfeld, S. (1993). Mannose 6-phosphateindependent targeting of lysosomal enzymes in I-cell disease B lymphoblasts. J. Cell Biol. 123, 99-108.
73. Goping, I. S., Sawchuk, T., Underhill, D. A., and Bleackley, R. C. (2006). Identification of {alpha}-tubulin as a granzyme B substrate during CTLmediated apoptosis. J. Cell. Sci. 119, 858-865.
74. Griffiths, G. M., and Isaaz, S. (1993). Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. J. Cell Biol. 120, 885-896.
75. Grom, A. A., Villanueva, J., Lee, S., Goldmuntz, E.A., Passo, M.H., and Filipovich, A. (2003). Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J. Pediatr. 142, 292-296.
76. Grossman, W. J., Revell, P. A., Lu, Z. H., Johnson, H., Bredemeyer, A. J., and Ley, T. J. (2003). The orphan granzymes of humans and mice. Curr. Opin. Immunol. 15, 544-552.
77. Heibein, J. A., Barry, M., Motyka, B., and Bleackley, R. C. (1999). Granzyme B-induced loss of mitochondrial inner membrane potential (Delta Psi m) and cytochrome c release are caspase independent. J. Immunol. 163, 4683-4693.
78. Horowitz, A., Stegmann, K. A., and Riley, E. M. (2011). Activation of natural killer cells during microbial infections. Front. Immun. 2:88. doi: 10.3389/fimmu.2011.00088
79. Hou, Q., Zhao, T., Zhang, H., Lu, H., Zhang, Q., Sun, L., et al. (2008). Granzyme H induces apoptosis of target tumor cells characterized by DNA fragmentation and Bid-dependent mitochondrial damage. Mol. Immunol. 45, 1044-1055.
80. Hsu, A. P., Sampaio, E. P., Khan, J., Calvo, K.R., Lemieux, J.E., Patel, S. Y., et al. (2011). Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118, 2653-2655.
81. Hua, G., Wang, S., Zhong, C., Xue, P., and Fan, Z. (2009). Ignition of p53 bomb sensitizes tumor cells to granzyme K-mediated cytolysis. J. Immunol. 182, 2152-2159.
82. Hua, G., Zhang, Q., and Fan, Z. (2007). Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis. J. Biol. Chem. 282, 20553-20560.
83. Hu, D., Liu, S., Shi, L., Li, C., Wu, L., and Fan, Z. (2010). Cleavage of survivin by Granzyme M triggers degradation of the survivin-Xlinked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells. J. Biol. Chem. 285, 18326-18335.
84. Ishii, E., Ueda, I., Shirakawa, R., Yamamoto, K., Horiuchi, H., Ohga, S., et al. (2005). Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 105, 3442-3448.
85. Jahn, R., and Scheller, R. H. (2006). SNAREs-engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7, 631-643.
86. Jiang, K., Zhong, B., Gilvary, D.L., Corliss, B. C., Hong-Geller, E., Wei, S., et al. (2000). Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Nat. Immunol. 1, 419-425.
87. Johnsen, A. C., Haux, J., Steinkjer, B., Nonstad, U., Egeberg, K., Sundan, A., et al. (1999). Regulation of APO-2 ligand/trail expression in NK cells-involvement in NK cellmediated cytotoxicity. Cytokine 11, 664-672.
88. Kam, C.M., Hudig, D., andPowers, J. C. (2000). Granzymes (lymphocyte serine proteases): characterization with natural and synthetic substrates and inhibitors. Biochim. Biophys. Acta 1477, 307-323.
89. Kanwar, N., and Wilkins, J. A. (2011). IQGAP1 involvement in MTOC and granule polarization in NK-cell cytotoxicity. Eur. J. Immunol. 41, 2763-2773.
90. Kaspar, A. A., Okada, S., Kumar, J., Poulain, F.R., Drouvalakis, K.A., Kelekar, A., et al. (2001). A distinct pathway of cell-mediated apoptosis initiated by granulysin. J. Immunol. 167, 350-356.
91. Kay, J. G., Murray, R. Z., Pagan, J. K., and Stow, J. L. (2006). Cytokine secretion via cholesterolrich lipid raft-associated SNAREs at the phagocytic cup. J. Biol. Chem. 281, 11949-11954.
92. Keefe, D., Shi, L., Feske, S., Massol, R., Navarro, F., Kirchhausen, T., et al. (2005). Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity 23, 249-262.
93. Kelly, J. M., Waterhouse, N. J., Cretney, E., Browne, K. A., Ellis, S., Trapani, J. A., et al. (2004). Granzyme M mediates a novel form of perforindependent cell death. J. Biol. Chem. 279, 22236-22242.
94. Kim, H. S., Das, A., Gross, C. C., Bryceson, Y.T., andLong, E.O. (2010). Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase. Immunity 32, 175-186.
95. Konjar, S., Sutton, V. R., Hoves, S., Repnik, U., Yagita, H., Reinheckel, T., et al. (2010). Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L. Immunology 131, 257-267.
96. Krensky, A. M., and Clayberger, C. (2009). Biology and clinical relevance of granulysin. Tissue Antigens 73, 193-198.
97. Krzewski, K., Chen, X., Orange, J. S., and Strominger, J. L. (2006). Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling. J. Cell Biol. 173, 121-132.
98. Krzewski, K., Chen, X., and Strominger, J. L. (2008). WIP is essential for lytic granule polarization and NK cell cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 105, 2568-2573.
99. Krzewski, K., Gil-Krzewska, A., Watts, J., Stern, J.N., andStrominger, J. L. (2011). VAMP4and VAMP7expressing vesicles are both required for cytotoxic granule exocytosis in NK cells. Eur. J. Immunol. 41, 3323-3329.
100. Krzewski, K., and Strominger, J. L. (2008). The killer's kiss: the many functions of NK cell immunological synapses. Curr. Opin. Cell Biol. 20, 597-605.
101. Kurowska, M., Goudin, N., Nehme, N. T., Court, M., Garin, J., Fischer, A., et al. (2012). Terminal transport of lytic granules to the immune synapse is mediated by the kinesin1/Slp3/Rab27a complex. Blood 119, 3879-3889.
102. Lanier, L. L. (2005). NK cell recognition. Annu. Rev. Immunol. 23, 225-274.
103. Lavrik, I. N., and Krammer, P. H. (2012). Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 19, 36-41.
104. Law, R. H., Lukoyanova, N., Voskoboinik, I., Caradoc-Davies, T. T., Baran, K., Dunstone, M. A., et al. (2010). The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468, 447-451.
105. Li, C., Ge, B., Nicotra, M., Stern, J. N. H., Kopcow, H. D., Chen, X., et al. (2008). JNK MAP kinase activation is required for MTOC and granule polarization in NKG2Dmediated NK cell cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 105, 3017-3022.
106. Liu, D., Bryceson, Y. T., Meckel, T., Vasiliver-Shamis, G., Dustin, M. L., and Long, E. O. (2009). Integrindependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity 31, 99-109.
107. Liu, D., Martina, J.A., Wu, X.S., Hammer, J. A. 3rd., and Long, E. O. (2011). Two modes of lytic granule fusion during degranulation by natural killer cells. Immunol. Cell Biol. 89, 728-738.
108. Liu, D., Meckel, T., and Long, E. O. (2010). Distinct role of rab27a in granule movement at the plasma membrane and in the cytosol of NK cells. PLoS ONE 5:e12870. doi: 10.1371/journal.pone.0012870
109. Logan, M. R., Lacy, P., Odemuyiwa, S. O., Steward, M., Davoine, F., Kita, H., et al. (2006). A critical role for vesicle-associated membrane protein-7 in exocytosis from human eosinophils and neutrophils. Allergy 61, 777-784.
110. Long, E. O. (2008). Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol. Rev. 224, 70-84.
111. Lu, H., Hou, Q., Zhao, T., Zhang, H., Zhang, Q., Wu, L., et al. (2006). Granzyme M directly cleaves inhibitor of caspase-activated DNase (CAD) to unleash CAD leading to DNA fragmentation. J. Immunol. 177, 1171-1178.
112. Mace, E. M., and Orange, J. S. (2012). Dual channel STED nanoscopy of lytic granules on actin filaments in natural killer cells. Commun. Integr. Biol. 5, 184-186.
113. Mahrus, S., Kisiel, W., and Craik, C. S. (2004). Granzyme M is a regulatory protease that inactivates proteinase inhibitor 9, an endogenous inhibitor of granzyme B. J. Biol. Chem. 279, 54275-54282.
114. Marcenaro, S., Gallo, F., Martini, S., Santoro, A., Griffiths, G. M., Arico, M., et al. (2006). Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Blood 108, 2316-2323.
115. Marcet-Palacios, M., Odemuyiwa, S. O., Coughlin, J. J., Garofoli, D., Ewen, C., Davidson, C. E., et al. (2008). Vesicle-associated membrane protein 7 (VAMP-7) is essential for target cell killing in a natural killer cell line. Biochem. Biophys. Res. Commun. 366, 617-623.
116. Martinvalet, D., Dykxhoorn, D. M., Ferrini, R., and Lieberman, J. (2008). Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 133, 681-692.
117. Martinvalet, D., Zhu, P., and Lieberman, J. (2005). Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 22, 355-370.
118. Masilamani, M., Nguyen, C., Kabat, J., Borrego, F., andColigan, J. E. (2006). CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. J. Immunol. 177, 3590-3596.
119. Maul-Pavicic, A., Chiang, S. C., Rensing-Ehl, A., Jessen, B., Fauriat, C., Wood, S. M., et al. (2011). ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. Proc. Natl. Acad. Sci. U.S.A. 108, 3324-3329.
120. McCann, F. E., Vanherberghen, B., Eleme, K., Carlin, L. M., Newsam, R. J., Goulding, D., et al. (2003). The size of the synaptic cleft and distinct distributions of filamentous actin, ezrin, CD43, and CD45 at activating and inhibitory human NK cell immune synapses. J. Immunol. 170, 2862-2870.
121. Meade, J. L., De Wynter, E. A., Brett, P., Sharif, S. M., Woods, C. G., Markham, A. F., et al. (2006). A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity. Blood 107, 3665-3668.
122. Medema, J. P., Toes, R. E., Scaffidi, C., Zheng, T.S., Flavell, R.A., Melief, C. J., et al. (1997). Cleavage of FLICE (caspase-8) by granzyme B during cytotoxic T lymphocyteinduced apoptosis. Eur. J. Immunol. 27, 3492-3498.
123. Meeths, M., Bryceson, Y. T., Rudd, E., Zheng, C., Wood, S.M., Ramme, K., et al. (2010). Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr. Blood Cancer 54, 563-572.
124. Meeths, M., Entesarian, M., Al-Herz, W., Chiang, S. C., Wood, S. M., AlAteeqi, W., et al. (2010). Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 116, 2635-2643.
125. Menager, M. M., Menasche, G., Romao, M., Knapnougel, P., Ho, C.H., Garfa, M., et al. (2007). Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-14. Nat. Immunol. 8, 257-267.
126. Mentlik, A. N., Sanborn, K. B., Holzbaur, E. L., and Orange, J. S. (2010). Rapid lytic granule convergence to the MTOC in natural killer cells is dependent on dynein but not cytolytic commitment. Mol. Biol. Cell 21, 2241-2256.
127. Metkar, S. S., Wang, B., Aguilar Santelises, M., Raja, S. M., Uhlin-Hansen, L., Podack, E., et al. (2002). Cytotoxic cell granulemediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 16, 417-428.
128. Metkar, S. S., Wang, B., Catalan, E., Anderluh, G., Gilbert, R. J., Pardo, J., et al. (2011). Perforin rapidly induces plasma membrane phospholipid flipflop. PLoS ONE 6:e24286. doi: 10.1371/journal.pone.0024286
129. Micucci, F., Capuano, C., Marchetti, E., Piccoli, M., Frati, L., Santoni, A., et al. (2008). PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway. Blood 111, 4165-4172.
130. Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., et al. (2004). Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J. Med. Genet. 41, 137-144.
131. Mollinedo, F., Calafat, J., Janssen, H., Martín-Martín, B., Canchado, J., Nabokina, S. M., et al. (2006). Combinatorial SNARE complexes modulate the secretion of cytoplasmic granules in human neutrophils. J. Immunol. 177, 2831-2841.
132. Monleon, I., Martinez-Lorenzo, M. J., Monteagudo, L., Lasierra, P., Taules, M., Iturralde, M., et al. (2001). Differential secretion of Fas ligandor APO2 ligand/TNFrelated apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J. Immunol. 167, 6736-6744.
133. Montel, A. H., Bochan, M. R., Hobbs, J.A., Lynch, D.H., andBrahmi, Z. (1995). Fas involvement in cytotoxicity mediated by human NK cells. Cell. Immunol. 166, 236-246.
134. Murray, R. Z., Wylie, F. G., Khromykh, T., Hume, D.A., andStow, J.L. (2005). Syntaxin 6 and Vti1b form a novel SNARE complex, which is upregulated in activated macrophages to facilitate exocytosis of tumor necrosis Factor-alpha. J. Biol. Chem. 280, 10478-10483.
135. Nakata, M., Kawasaki, A., Azuma, M., Tsuji, K., Matsuda, H., Shinkai, Y., et al. (1992). Expression of perforin and cytolytic potential of human peripheral blood lymphocyte subpopulations. Int. Immunol. 4, 1049-1054.
136. Nedvetzki, S., Sowinski, S., Eagle, R. A., Harris, J., Vély, F., Pende, D., et al. (2007). Reciprocal regulation of human natural killer cells and macrophages associated with distinct immune synapses. Blood 109, 3776-3785.
137. Neighbour, P. A., Huberman, H. S., and Kress, Y. (1982). Human large granular lymphocytes and natural killing ultrastructural studies of strontium-induced degranulation. Eur. J. Immunol. 12, 588-595.
138. Nishino, I. (2003). Autophagic vacuolar myopathies. Curr. Neurol. Neurosci. Rep. 3, 64-69.
139. Nishino, I., Fu, J., Tanji, K., Yamada, T., Shimojo, S., Koori, T., et al. (2000). Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906-910.
140. Obata-Onai, A., Hashimoto, S., Onai, N., Kurachi, M., Nagai, S., Shizuno, K., et al. (2002). Comprehensive gene expression analysis of human NK cells and CD8(+) T lymphocytes. Int. Immunol. 14, 1085-1098.
141. Okada, S., Li, Q., Whitin, J. C., Clayberger, C., and Krensky, A. M. (2003). Intracellular mediators of granulysin-induced cell death. J. Immunol. 171, 2556-2562.
142. Orange, J. S. (2002). Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 4, 1545-1558.
143. Orange, J. S. (2006). Human natural killer cell deficiencies. Curr. Opin. Allergy Clin. Immunol. 6, 399-409.
144. Orange, J. S. (2008). Formation and function of the lytic NK-cell immunological synapse. Nat. Rev. Immunol. 8, 713-725.
145. Orange, J. S., and Ballas, Z. K. (2006). Natural killer cells in human health and disease. Clin. Immunol. 118, 1-10.
146. Orange, J.S., Harris, K.E., Andzelm, M. M., Valter, M. M., Geha, R. S., and Strominger, J. L. (2003). The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc. Natl. Acad. Sci. U.S.A. 100, 14151-14156.
147. Orange, J. S., Ramesh, N., Remold O'Donnell, E., Sasahara, Y., Koopman, L., Byrne, M., et al. (2002). Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc. Natl. Acad. Sci. U.S.A. 99, 11351-11356.
148. Pagan, J. K., Wylie, F. G., Joseph, S., Widberg, C., Bryant, N.J., James, D. E., et al. (2003). The t-SNARE syntaxin 4 is regulated during macrophage activation to function in membrane traffic and cytokine secretion. Curr. Biol. 13, 156-160.
149. Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A. K., et al. (2012). Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood 119, 6016-6024.
150. Perez, O. D., Mitchell, D., Jager, G. C., and Nolan, G. P. (2004). LFA1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. Blood 104, 1083-1093.
151. Perrin, B. J., Amann, K. J., and Huttenlocher, A. (2006). Proteolysis of cortactin by calpain regulates membrane protrusion during cell migration. Mol. Biol. Cell 17, 239-250.
152. Peters, P. J., Borst, J., Oorschot, V., Fukuda, M., Krahenbuhl, O., Tschopp, J., et al. (1991). Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J. Exp. Med. 173, 1099-1109.
153. Pinkoski, M. J., Waterhouse, N. J., Heibein, J. A., Wolf, B. B., Kuwana, T., Goldstein, J. C., et al. (2001). Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. J. Biol. Chem. 276, 12060-12067.
154. Poe, M., Blake, J.T., Boulton, D.A., Gammon, M., Sigal, N.H., Wu, J. K., et al. (1991). Human cytotoxic lymphocyte granzyme B. Its purification from granules and the characterization of substrate and inhibitor specificity. J. Biol. Chem. 266, 98-103.
155. Pollard, T.D., andCooper, J.A. (2009). Actin, a central player in cell shape and movement. Science 326, 1208-1212.
156. Portales, P., Reynes, J., Pinet, V., Rouzier-Panis, R., Baillat, V., Clot, J., et al. (2003). Interferon-alpha restores HIV-induced alteration of natural killer cell perforin expression in vivo. AIDS 17, 495-504.
157. Potter, D. A., Tirnauer, J. S., Janssen, R., Croall, D. E., Hughes, C. N., Fiacco, K. A., et al. (1998). Calpain regulates actin remodeling during cell spreading. J. Cell Biol. 141, 647-662.
158. Praper, T., Sonnen, A., Viero, G., Kladnik, A., Froelich, C. J., Anderluh, G., et al. (2011). Human perforin employs different avenues to damage membranes. J. Biol. Chem. 286, 2946-2955.
159. Praper, T., Sonnen, A. F., Kladnik, A., Andrighetti, A. O., Viero, G., Morris, K. J., et al. (2011). Perforin activity at membranes leads to invaginations and vesicle formation. Proc. Natl. Acad. Sci. U.S.A. 108, 21016-21021.
160. Puri, N., and Roche, P. A. (2006). Ternary SNARE complexes are enriched in lipid rafts during mast cell exocytosis. Traffic 7, 1482-1494.
161. Raja, S. M., Wang, B., Dantuluri, M., Desai, U. R., Demeler, B., Spiegel, K., et al. (2002). Cytotoxic cell granule-mediated apoptosis. Characterization of the macromolecular complex of granzyme B with serglycin. J. Biol. Chem. 277, 49523-49530.
162. Rak, G. D., Mace, E. M., Banerjee, P. P., Svitkina, T., andOrange, J.S. (2011). Natural killer cell lytic granule secretion occurs through a pervasive actin network at the immune synapse. PLoS Biol. 9:e1001151. doi: 10.1371/journal.pbio.1001151
163. Ramoni, C., Luciani, F., Spadaro, F., Lugini, L., Lozupone, F., and Fais, S. (2002). Differential expression and distribution of ezrin, radixin and moesin in human natural killer cells. Eur. J. Immunol. 32, 3059-3065.
164. Riteau, B., Barber, D. F., and Long, E. O. (2003). Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. J. Exp. Med. 198, 469-474.
165. Robertson, M. J. (2002). Role of chemokines in the biology of natural killer cells. J. Leukoc. Biol. 71, 173-183.
166. Rochel, N., and Cowan, J. (1996). Negative cooperativity exhibited by the lytic amino-terminal domain of human perforin: implications for perforin-mediated cell lysis. Chem. Biol. 3, 31-36.
167. Roda-Navarro, P., Mittelbrunn, M., Ortega, M., Howie, D., Terhorst, C., Sánchez-Madrid, F., et al. (2004). Dynamic redistribution of the activating 2B4/SAP complex at the cytotoxic NK cell immune synapse. J. Immunol. 173, 3640-3646.
168. Rohr, J., Beutel, K., Maul-Pavicic, A., Vraetz, T., Thiel, J., Warnatz, K., et al. (2010). Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D andSTXBP2overlapswithprimary immunodeficiency diseases. Haematologica 95, 2080-2087.
169. Saftig, P., and Klumperman, J. (2009). Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10, 623-635.
170. Saini, R. V., Wilson, C., Finn, M. W., Wang, T., Krensky, A.M., and Clayberger, C. (2011). Granulysin delivered by cytotoxic cells damages endoplasmic reticulum and activates caspase-7 in target cells. J. Immunol. 186, 3497-3504.
171. Salcedo, T. W., Azzoni, L., Wolf, S. F., and Perussia, B. (1993). Modulation of perforin and granzyme messenger RNA expression in human natural killer cells. J. Immunol. 151, 2511-2520.
172. Sanborn, K. B., Mace, E. M., Rak, G. D., Difeo, A., Martignetti, J. A., Pecci, A., et al. (2011). Phosphorylation of the myosin IIA tailpiece regulates single myosin IIA molecule association with lytic granules to promote NK-cell cytotoxicity. Blood 118, 5862-5871.
173. Sanborn, K.B., Rak, G.D., Maru, S.Y., Demers, K., Difeo, A., Martignetti, J. A., et al. (2009). Myosin IIA associates with NK cell lytic granules to enable their interaction with Factin and function at the immunological synapse. J. Immunol. 182, 6969-6984.
174. Sancho, D., Nieto, M., Llano, M., Rodríguez-Fernández, J. L., Tejedor, R., Avraham, S., et al. (2000). The tyrosine kinase PYK-2/RAFTK regulates natural killer (NK) cell cytotoxic response, and is translocated and activated upon specific target cell recognition and killing. J. Cell Biol. 149, 1249-1262.
175. Schmidt, H., Gelhaus, C., Lucius, R., Nebendahl, M., Leippe, M., and Janssen, O. (2009). Enrichment and analysis of secretory lysosomes from lymphocyte populations. BMC Immunol. 10:41. doi: 10.1186/1471-2172-10-41
176. Schmidt, H., Gelhaus, C., Nebendahl, M., Lettau, M., Lucius, R., Leippe, M., et al. (2011). Effector granules in human T lymphocytes: proteomic evidence for two distinct species of cytotoxic effector vesicles. J. Proteome Res. 10, 1603-1620.
177. Sebbagh, M., Hamelin, J., Bertoglio, J., Solary, E., and Breard, J. (2005). Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspaseindependent manner. J. Exp. Med. 201, 465-471.
178. Segovis, C. M., Schoon, R. A., Dick, C. J., Nacusi, L. P., Leibson, P. J., and Billadeau, D. D. (2009). PI3K links NKG2D signaling to a CrkL pathway involved in natural killer cell adhesion, polarity, and granule secretion. J. Immunol. 182, 6933-6942.
179. Sharif-Askari, E., Alam, A., Rheaume, E., Beresford, P. J., Scotto, C., Sharma, K., et al. (2001). Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation. EMBO J. 20, 3101-3113.
180. Shuster, C. B., and Herman, I. M. (1995). Indirect association of ezrin with F-actin: isoform specificity and calcium sensitivity. J. Cell Biol. 128, 837-848.
181. Smyth, M. J., McGuire, M. J., and Thia, K. Y. (1995). Expression of recombinant human granzyme B. A processing and activation role for dipeptidyl peptidase I. J. Immunol. 154, 6299-6305.
182. Stenger, S., Hanson, D. A., Teitelbaum, R., Dewan, P., Niazi, K. R., Froelich, C. J., et al. (1998). An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282, 121-125.
183. Stewart, M. P., McDowall, A., and Hogg, N. (1998). LFA-1-mediated adhesion is regulated by cytoskeletal restraint and by a Ca2+-dependent protease, calpain. J. Cell Biol. 140, 699-707.
184. Stinchcombe, J. C., Majorovits, E., Bossi, G., Fuller, S., and Griffiths, G. M. (2006). Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443, 462-465.
185. Stinchcombe, J. C., Salio, M., Cerundolo, V., Pende, D., Arico, M., and Griffiths, G. M. (2011). Centriole polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems. BMC Biol. 9:45. doi: 10.1186/1741-7007-9-45
186. Sutton, V. R., Davis, J. E., Cancilla, M., Johnstone, R.W., Ruefli, A.A., Sedelies, K., et al. (2000). Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J. Exp. Med. 192, 1403-1414.
187. Tewary, P., Yang, D., DeLaRosa, G., Li, Y., Finn, M.W., Krensky, A.M., et al. (2010). Granulysin activates antigen-presenting cells through TLR4 and acts as an immune alarmin. Blood 116, 3465-3474.
188. Thiery, J., Keefe, D., Boulant, S., Boucrot, E., Walch, M., Martinvalet, D., et al. (2011). Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. Nat. Immunol. 12, 770-777.
189. Thiery, J., Keefe, D., Saffarian, S., Martinvalet, D., Walch, M., Boucrot, E., et al. (2010). Perforin activates clathrinand dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzymemediated apoptosis. Blood 115, 1582-1593.
190. Uellner, R., Zvelebil, M. J., Hopkins, J., Jones, J., Macdougall, L. K., Morgan, B. P., et al. (1997). Perforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipidbinding C2 domain. EMBO J. 16, 7287-7296.
191. Upshaw, J. L., Arneson, L. N., Schoon, R. A., Dick, C. J., Billadeau, D. D., and Leibson, P. J. (2006). NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat. Immunol. 7, 524-532.
192. Valdez, A. C., Cabaniols, J. P., Brown, M. J., and Roche, P. A. (1999). Syntaxin 11 is associated with SNAP-23 on late endosomes and the trans-Golgi network. J. Cell. Sci. 112 (Pt 6), 845-854.
193. van der Spoel, A., Bonten, E., and d'Azzo, A. (1998). Transport of human lysosomal neuraminidase to mature lysosomes requires protective protein/cathepsin A. EMBO J. 17, 1588-1597.
194. Villanueva, J., Lee, S., Giannini, E. H., Graham, T.B., Passo, M. H., Filipovich, A., et al. (2005). Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res. Ther. 7, R30-R37.
195. Vivier, E., Tomasello, E., Baratin, M., Walzer, T., and Ugolini, S. (2008). Functions of natural killer cells. Nat. Immunol. 9, 503-510.
196. Voskoboinik, I., Dunstone, M. A., Baran, K., Whisstock, J. C., and Trapani, J. A. (2010). Perforin: structure, function, and role in human immunopathology. Immunol. Rev. 235, 35-54.
197. Voskoboinik, I., Smyth, M. J., and Trapani, J. A. (2006). Perforinmediated target-cell death and immune homeostasis. Nat. Rev. Immunol. 6, 940-952.
198. Voskoboinik, I., Thia, M. C., De Bono, A., Browne, K., Cretney, E., Jackson, J. T., et al. (2004). The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J. Exp. Med. 200, 811-816.
199. Voskoboinik, I., Thia, M. C., Fletcher, J., Ciccone, A., Browne, K., Smyth, M. J., et al. (2005). Calciumdependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: a critical role for aspartate residues 429 435 483, and 485 but not 491. J. Biol. Chem. 280, 8426-8434.
200. Voskoboinik, I., Thia, M. C., and Trapani, J. A. (2005). A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood 105, 4700-4706.
201. Vyas, Y. M., Maniar, H., and Dupont, B. (2002). Visualization of signaling pathways and cortical cytoskeleton in cytolytic and noncytolytic natural killer cell immune synapses. Immunol. Rev. 189, 161-178.
202. Vyas, Y.M., Mehta, K.M., Morgan, M., Maniar, H., Butros, L., Jung, S., et al. (2001). Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class Iregulated noncytolytic and cytolytic interactions. J. Immunol. 167, 4358-4367.
203. Wang, S., Xia, P., Shi, L., andFan, Z. (2012). FADD cleavage by NK cell granzyme M enhances its self-association to facilitate procaspase-8 recruitment for auto-processing leading to caspase cascade. Cell Death Differ. 19, 605-615.
204. Watzl, C., Stebbins, C.C., andLong, E. O. (2000). NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244). J. Immunol. 165, 3545-3548.
205. Watzl, C., and Urlaub, D. (2012). Molecular mechanisms of natural killer cell regulation. Front. Biosci. 17, 1418-1432.
206. Werneburg, N. W., Bronk, S. F., Guicciardi, M. E., Thomas, L., Dikeakos, J. D., Thomas, G., et al. (2012). Tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) protein-induced lysosomal translocation of proapoptotic effectors is mediated by phosphofurin acidic cluster sorting protein-2 (PACS-2). J. Biol. Chem. 287, 24427-24437.
207. Wiedemann, A., Depoil, D., Faroudi, M., and Valitutti, S. (2006). Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses. Proc. Natl. Acad. Sci. U.S.A. 103, 10985-10990.
208. Wood, S.M., Ljunggren, H.G., and Bryceson, Y. T. (2011). Insights into NK cell biology from human genetics and disease associations. Cell. Mol. Life Sci. 68, 3479-3493.
209. Wood, S. M., Meeths, M., Chiang, S. C., Bechensteen, A. G., Boelens, J. J., Heilmann, C., et al. (2009). Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity. Blood 114, 4117-4127.
210. Wulfing, C., Purtic, B., Klem, J., and Schatzle, J. D. (2003). Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing. Proc. Natl. Acad. Sci. U.S.A. 100, 7767-7772.
211. Zamai, L., Ahmad, M., Bennett, I.M., Azzoni, L., Alnemri, E. S., and Perussia, B. (1998). Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J. Exp. Med. 188, 2375-2380.
212. Zhang, D., Beresford, P. J., Greenberg, A. H., and Lieberman, J. (2001). Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis. Proc. Natl. Acad. Sci. U.S.A. 98, 5746-5751.
213. Zhang, D., Pasternack, M. S., Beresford, P. J., Wagner, L., Greenberg, A. H., and Lieberman, J. (2001). Induction of rapid histone degradation by the cytotoxic T lymphocyte protease Granzyme, A. J. Biol. Chem. 276, 3683-3690.
214. Zhang, H., Zhong, C., Shi, L., Guo, Y., and Fan, Z. (2009). Granulysin induces cathepsin B release from lysosomes of target tumor cells to attack mitochondria through processing of bid leading to Necroptosis. J. Immunol. 182, 6993-7000.
215. Zhao, T., Zhang, H., Guo, Y., and Fan, Z. (2007). Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death. J. Biol. Chem. 282, 12104-12111.
216. Zhao, T., Zhang, H., Guo, Y., Zhang, Q., Hua, G., Lu, H., et al. (2007). Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells. Cell Death Differ. 14, 489-499.
217. Zhu, P., Martinvalet, D., Chowdhury, D., Zhang, D., Schlesinger, A., and Lieberman, J. (2009). The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphateribose) polymerase-1. Blood 114, 1205-1216.
218. Zhu, P., Zhang, D., Chowdhury, D., Martinvalet, D., Keefe, D., Shi, L., et al. (2006). Granzyme, A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70. EMBO Rep. 7, 431-437.
219. Zuccato, E., Blott, E. J., Holt, O., Sigismund, S., Shaw, M., Bossi, G., et al. (2007). Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation. J. Cell. Sci. 120, 191-199.
220. Zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., et al. (2009). Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am.J.Hum.Genet.85, 482-492.