Perforin and granzymes: Function, dysfunction and human pathology

Nature Reviews Immunology

Volumn 15, Issue 6, 2015, Pages 388-400

  Voskoboinik, Ilia ^a,b   Whisstock, James C ^c   Trapani, Joseph A ^a,b  

^a PETER MACCALLUM CANCER CENTRE   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOLYSIN; DIPEPTIDYL PEPTIDASE I; GRANULYSIN; GRANZYME; GRANZYME A; GRANZYME B; PERFORIN; PHOSPHATIDYLSERINE; PROPIDIUM IODIDE; SERINE PROTEINASE;

CELL DEATH; CHANNEL GATING; CYTOSOL; CYTOTOXIC LYMPHOCYTE; CYTOTOXIC T LYMPHOCYTE; CYTOTOXICITY; ENZYME STRUCTURE; EXOCYTOSIS; GENE MUTATION; HUMAN; IMMUNOLOGICAL SYNAPSE; IMMUNOPATHOLOGY; IMMUNOREGULATION; IMMUNOTHERAPY; INFECTION; INFLAMMATION; MICROTUBULE ORGANIZING CENTER; NATURAL KILLER CELL; NONHUMAN; OLIGOMERIZATION; PRIORITY JOURNAL; REVIEW; TARGET CELL; TOXIC EPIDERMAL NECROLYSIS; TUMOR IMMUNITY; WISKOTT ALDRICH SYNDROME; ANIMAL; APOPTOSIS; CELL COMMUNICATION; CHEMISTRY; ENDOSOME; GENETIC POLYMORPHISM; GENETICS; IMMUNOLOGY; NEOPLASM; PHYSIOLOGY; SECRETORY VESICLE;

ANIMALS; APOPTOSIS; CELL COMMUNICATION; CYTOSOL; ENDOSOMES; EXOCYTOSIS; GRANZYMES; HUMANS; IMMUNE SYSTEM DISEASES; INFECTION; INFLAMMATION; KILLER CELLS, NATURAL; NEOPLASMS; PERFORIN; POLYMORPHISM, GENETIC; SECRETORY VESICLES; T-LYMPHOCYTES, CYTOTOXIC;

EID: 84929961969     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri3839     Document Type: Review

References (189)

1. Ritter, A. T., Angus, K. L. & Griffiths, G. M. The role of the cytoskeleton at the immunological synapse. Immunol. Rev. 256, 107-117 (2013).
2. Voskoboinik, I. & Trapani, J. A. Perforinopathy: a spectrum of human immune disease caused by defective perforin delivery or function. Front. Immunol. 4, 441 (2013).
3. Brennan, A. J., Chia, J., Trapani, J. A. & Voskoboinik, I. Perforin deficiency and susceptibility to cancer. Cell Death Differ. 17, 607-615 (2010).
4. de Saint Basile, G., Ménasché, G. & Fischer, A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nature Rev. Immunol. 10, 568-579 (2010).
5. Janka, G. E. Familial and acquired hemophagocytic lymphohistiocytosis. Annu. Rev. Med. 63, 233-246 (2012).
6. Rosenau, W. & Moon, H. D. Lysis of homologous cells by sensitized lymphocytes in tissue culture. J. Natl Cancer Inst. 27, 471-483 (1961).
7. Bykovskaja, S. N., Rytenko, A. N., Rauschenbach, M. O. & Bykovsky, A. F. Ultrastructural alteration of cytolytic T lymphocytes following their interaction with target cells. II. Morphogenesis of secretory granules and intracellular vacuoles. Cell. Immunol. 40, 175-185 (1978).
8. Bykovskaja, S. N., Rytenko, A. N., Rauschenbach, M. O. & Bykovsky, A. F. Ultrastructural alteration of cytolytic T lymphocytes following their interaction with target cells. I. Hypertrophy and change of orientation of the Golgi apparatus. Cell. Immunol. 40, 164-174 (1978).
9. Yannelli, J. R., Sullivan, J. A., Mandell, G. L. & Engelhard, V. H. Reorientation and fusion of cytotoxic T lymphocyte granules after interaction with target cells as determined by high resolution cinemicrography. J. Immunol. 136, 377-382 (1986).
10. Dourmashkin, R. R., Deteix, P., Simone, C. B. & Henkart, P. Electron microscopic demonstration of lesions in target cell membranes associated with antibody-dependent cellular cytotoxicity. Clin. Exp. Immunol. 42, 554-560 (1980).
11. Henkart, P. A., Millard, P. J., Reynolds, C. W. & Henkart, M. P. Cytolytic activity of purified cytoplasmic granules from cytotoxic rat large granular lymphocyte tumors. J. Exp. Med. 160, 75-93 (1984).
12. Millard, P. J., Henkart, M. P., Reynolds, C. W. & Henkart, P. A. Purification and properties of cytoplasmic granules from cytotoxic rat LGL tumors. J. Immunol. 132, 3197-3204 (1984).
13. Shinkai, Y., Takio, K. & Okumura, K. Homology of perforin to the ninth component of complement (C9). Nature 334, 525-527 (1988).
14. Podack, E. R., Young, J. D. & Cohn, Z. A. Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules. Proc. Natl Acad. Sci. USA 82, 8629-8633 (1985).
15. Young, J. D., Cohn, Z. A. & Podack, E. R. The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: structural, immunological, and functional similarities. Science 233, 184-190 (1986).
16. Young, J. D., Hengartner, H., Podack, E. R. & Cohn, Z. A. Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity. Cell 44, 849-859 (1986).
17. Jenne, D. et al. Identification and sequencing of cDNA clones encoding the granule-associated serine proteases granzymes D, E and F of cytolytic T lymphocytes. Proc. Natl Acad. Sci. USA 85, 4814-4818 (1988).
18. Masson, D. & Tschopp, J. A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell 49, 679-685 (1987).
19. Krahenbuhl, O. et al. Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes. J. Immunol. 141, 3471-3477 (1988).
20. Young, J. D. et al. Isolation and characterization of a serine esterase from cytolytic T cell granules. Cell 47, 183-194 (1986).
21. Shi, L., Kam, C. M., Powers, J. C., Aebersold, R. & Greenberg, A. H. Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions. J. Exp. Med. 176, 1521-1529 (1992).
22. Nakajima, H. & Henkart, P. A. Cytotoxic lymphocyte granzymes trigger a target cell internal disintegration pathway leading to cytolysis and DNA breakdown. J. Immunol. 152, 1057-1063 (1994).
23. Shi, L. et al. Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization. J. Exp. Med. 185, 855-866 (1997).
24. Nakajima, H., Park, H. L. & Henkart, P. A. Synergistic roles of granzymes A and B in mediating target cell death by rat basophilic leukemia mast cell tumors also expressing cytolysin/perforin. J. Exp. Med. 181, 1037-1046 (1995).
25. Shiver, J. W., Su, L. & Henkart, P. A. Cytotoxicity with target DNA breakdown by rat basophilic leukemia cells expressing both cytolysin and granzyme A. Cell 71, 315-322 (1992).
26. Heusel, J. W., Wesselschmidt, R. L., Shresta, S., Russell, J. H. & Ley, T. J. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 76, 977-987 (1994).
27. Su, B., Bochan, M. R., Hanna, W. L., Froelich, C. J. & Brahmi, Z. Human granzyme B is essential for DNA fragmentation of susceptible target cells. Eur. J. Immunol. 24, 2073-2080 (1994).
28. Trapani, J. A. & Smyth, M. J. Killing by cytotoxic T cells and natural killer cells: multiple granule serine proteases as initiators of DNA fragmentation. Immunol. Cell Biol. 71, 201-208 (1993).
29. Jongstra, J. et al. The isolation and sequence of a novel gene from a human functional T cell line. J. Exp. Med. 165, 601-614 (1987).
30. Peters, P. J. et al. Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J. Exp. Med. 173, 1099-1109 (1991).
31. Bolitho, P., Voskoboinik, I., Trapani, J. A. & Smyth, M. J. Apoptosis induced by the lymphocyte effector molecule perforin. Curr. Opin. Immunol. 19, 339-347 (2007).
32. Voskoboinik, I., Smyth, M. J. & Trapani, J. A. Perforin-mediated target-cell death and immune homeostasis. Nature Rev. Immunol. 6, 940-952 (2006).
33. Mullbacher, A., Hla, R. T., Museteanu, C. & Simon, M. M. Perforin is essential for control of ectromelia virus but not related poxviruses in mice. J. Virol. 73, 1665-1667 (1999).
34. Pardo, J., Balkow, S., Anel, A. & Simon, M. M. The differential contribution of granzyme A and granzyme B in cytotoxic T lymphocyte-mediated apoptosis is determined by the quality of target cells. Eur. J. Immunol. 32, 1980-1985 (2002).
35. Simon, M. M. et al. In vitro-and ex vivo-derived cytolytic leukocytes from granzyme A x B double knockout mice are defective in granule-mediated apoptosis but not lysis of target cells. J. Exp. Med. 186, 1781-1786 (1997).
36. Stepp, S. E. et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286, 1957-1959 (1999).
37. Pipkin, M. E. et al. Chromosome transfer activates and delineates a locus control region for perforin. Immunity 26, 29-41 (2007).
38. Pipkin, M. E., Rao, A. & Lichtenheld, M. G. The transcriptional control of the perforin locus. Immunol. Rev. 235, 55-72 (2010).
39. Cruz-Guilloty, F. et al. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J. Exp. Med. 206, 51-59 (2009).
40. Pipkin, M. E. et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32, 79-90 (2010).
41. Kim, N. et al. MicroRNA-150 regulates the cytotoxicity of natural killers by targeting perforin-1. J. Allergy Clin. Immunol. 134, 195-203 (2014).
42. Kim, T. D. et al. Human microRNA-27a∗targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity. Blood 118, 5476-5486 (2011).
43. Trifari, S. et al. MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation. Proc. Natl Acad. Sci. USA 110, 18608-18613 (2013).
44. Wang, P. et al. Identification of resting and type I IFN-activated human NK cell miRNomes reveals microRNA-378 and microRNA-30e as negative regulators of NK cell cytotoxicity. J. Immunol. 189, 211-221 (2012).
45. D'Angelo, M. E. et al. Cathepsin H is an additional convertase of pro-granzyme B. J. Biol. Chem. 285, 20514-20519 (2010).
46. Pham, C. T. & Ley, T. J. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc. Natl Acad. Sci. USA 96, 8627-8632 (1999).
47. Griffiths, G. M. & Isaaz, S. Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. J. Cell Biol. 120, 885-896 (1993).
48. Young, J. D., Damiano, A., DiNome, M. A., Leong, L. G. & Cohn, Z. A. Dissociation of membrane binding and lytic activities of the lymphocyte pore-forming protein (perforin). J. Exp. Med. 165, 1371-1382 (1987).
49. Voskoboinik, I. et al. Calcium-dependent 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 (2005).
50. Praper, T. et al. Human perforin permeabilizing activity, but not binding to lipid membranes, is affected by pH. Mol. Immunol. 47, 2492-2504 (2010).
51. Uellner, R. et al. Perforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipid-binding C2 domain. EMBO J. 16, 7287-7296 (1997).
52. Brennan, A. J. et al. Protection from endogenous perforin: glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes. Immunity 34, 879-892 (2011).
53. Law, R. H. et al. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468, 447-451 (2010).
54. Lopez, J. A., Brennan, A. J., Whisstock, J. C., Voskoboinik, I. & Trapani, J. A. Protecting a serial killer: pathways for perforin trafficking and self-defence ensure sequential target cell death. Trends Immunol. 33, 406-412 (2012).
55. Krzewski, K., Gil-Krzewska, A., Nguyen, V., Peruzzi, G. & Coligan, J. E. LAMP1/CD107a is required for efficient perforin delivery to lytic granules and NK-cell cytotoxicity. Blood 121, 4672-4683 (2013).
56. Dustin, M. L. & Long, E. O. Cytotoxic immunological synapses. Immunol. Rev. 235, 24-34 (2010).
57. Lagrue, K. et al. The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse. Immunol. Rev. 256, 203-221 (2013).
58. Stinchcombe, J. C., Majorovits, E., Bossi, G., Fuller, S. & Griffiths, G. M. Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443, 462-465 (2006).
59. Bertrand, F. et al. An initial and rapid step of lytic granule secretion precedes microtubule organizing center polarization at the cytotoxic T lymphocyte/target cell synapse. Proc. Natl Acad. Sci. USA 110, 6073-6078 (2013).
60. Ruiz-Garcia, R. et al. A case of partial dedicator of cytokinesis 8 deficiency with altered effector phenotype and impaired CD8+ and natural killer cell cytotoxicity. J. Allergy Clin. Immunol. 134, 218-221 (2014).
61. Randall, K. L. et al. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J. Exp. Med. 208, 2305-2320 (2011).
62. Kupfer, A., Singer, S. J. & Dennert, G. On the mechanism of unidirectional killing in mixtures of two cytotoxic T lymphocytes. Unidirectional polarization of cytoplasmic organelles and the membrane-associated cytoskeleton in the effector cell. J. Exp. Med. 163, 489-498 (1986).
63. Balaji, K. N., Schaschke, N., Machleidt, W., Catalfamo, M. & Henkart, P. A. Surface cathepsin B protects cytotoxic lymphocytes from self-destruction after degranulation. J. Exp. Med. 196, 493-503 (2002).
64. Baran, K. et al. Cytotoxic T lymphocytes from cathepsin B-deficient mice survive normally in vitro and in vivo after encountering and killing target cells. J. Biol. Chem. 281, 30485-30491 (2006).
65. Lopez, J. A. et al. Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood 121, 2659-2668 (2013).
66. Isaaz, S., Baetz, K., Olsen, K., Podack, E. & Griffiths, G. M. Serial killing by cytotoxic T lymphocytes: T cell receptor triggers degranulation, re-filling of the lytic granules and secretion of lytic proteins via a non-granule pathway. Eur. J. Immunol. 25, 1071-1079 (1995).
67. Cohnen, A. et al. Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage. Blood 122, 1411-1418 (2013).
68. Bird, C. H. et al. Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol. Cell. Biol. 18, 6387-6398 (1998).
69. Zhang, M. et al. Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules. Immunity 24, 451-461 (2006).
70. Hadders, M. A., Beringer, D. X. & Gros, P. Structure of C8?-MACPF reveals mechanism of membrane attack in complement immune defense. Science 317, 1552-1554 (2007).
71. Rosado, C. J. et al. A common fold mediates vertebrate defense and bacterial attack. Science 317, 1548-1551 (2007).
72. Slade, D. J. et al. Crystal structure of the MACPF domain of human complement protein C8? in complex with the C8? subunit. J. Mol. Biol. 379, 331-342 (2008).
73. Shatursky, O. et al. The mechanism of membrane insertion for a cholesterol-dependent cytolysin: a novel paradigm for pore-forming toxins. Cell 99, 293-299 (1999).
74. Tilley, S. J., Orlova, E. V., Gilbert, R. J., Andrew, P. W. & Saibil, H. R. Structural basis of pore formation by the bacterial toxin pneumolysin. Cell 121, 247-256 (2005).
75. Reboul, C. F., Mahmood, K., Whisstock, J. C. & Dunstone, M. A. Predicting giant transmembrane ?-barrel architecture. Bioinformatics 28, 1299-1302 (2012).
76. Gilbert, R. J., Dalla Serra, M., Froelich, C. J., Wallace, M. I. & Anderluh, G. Membrane pore formation at protein-lipid interfaces. Trends Biochem. Sci. 39, 510-516 (2014).
77. Leung, C. et al. Stepwise visualization of membrane pore formation by suilysin, a bacterial cholesterol-dependent cytolysin. eLife 3, e04247 (2014).
78. Metkar, S. S. et al. Perforin oligomers form arcs in cellular membranes: a locus for intracellular delivery of granzymes. Cell Death Differ. 22, 74-85 (2015).
79. Voskoboinik, I., Dunstone, M. A., Baran, K., Whisstock, J. C. & Trapani, J. A. Perforin: structure, function, and role in human immunopathology. Immunol. Rev. 235, 35-54 (2010).
80. Baran, K. et al. The molecular basis for perforin oligomerization and transmembrane pore assembly. Immunity 30, 684-695 (2009).
81. Browne, K. A. et al. Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol. Cell. Biol. 19, 8604-8615 (1999).
82. Keefe, D. et al. Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity 23, 249-262 (2005).
83. Froelich, C. J. et al. 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 (1996).
84. Metkar, S. S. et al. Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 16, 417-428 (2002).
85. Thiery, J. et al. Perforin activates clathrin-and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis. Blood 115, 1582-1593 (2010).
86. Thiery, J. et al. Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. Nature Immunol. 12, 770-777 (2011).
87. Gerasimenko, J. V., Tepikin, A. V., Petersen, O. H. & Gerasimenko, O. V. Calcium uptake via endocytosis with rapid release from acidifying endosomes. Curr. Biol. 8, 1335-1338 (1998).
88. Metkar, S. S. et al. Perforin rapidly induces plasma membrane phospholipid flip-flop. PLoS ONE 6, e24286 (2011).
89. Renkin, E. M. Filtration, diffusion, and molecular sieving through porous cellulose membranes. J. Gen. Physiol. 38, 225-243 (1954).
90. Lopez, J. A. et al. Rapid and unidirectional perforin pore delivery at the cytotoxic immune synapse. J. Immunol. 191, 2328-2334 (2013).
91. Reddy, A., Caler, E. V. & Andrews, N. W. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell 106, 157-169 (2001).
92. Gilbert, R. J. Inactivation and activity of cholesterol-dependent cytolysins: what structural studies tell us. Structure 13, 1097-1106 (2005).
93. McNeil, P. L. & Steinhardt, R. A. Plasma membrane disruption: repair, prevention, adaptation. Annu. Rev. Cell Dev. Biol. 19, 697-731 (2003).
94. Shi, L., Kraut, R. P., Aebersold, R. & Greenberg, A. H. A natural killer cell granule protein that induces DNA fragmentation and apoptosis. J. Exp. Med. 175, 553-566 (1992).
95. Hiebert, P. R. & Granville, D. J. Granzyme B in injury, inflammation, and repair. Trends Mol. Med. 18, 732-741 (2012).
96. Andrade, F., Fellows, E., Jenne, D. E., Rosen, A. & Young, C. S. Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition. EMBO J. 26, 2148-2157 (2007).
97. Pham, C. T., Ivanovich, J. L., Raptis, S. Z., Zehnbauer, B. & Ley, T. J. Papillon-Lef?re syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J. Immunol. 173, 7277-7281 (2004).
98. Sutton, V. R. & Trapani, J. A. Proteases in lymphocyte killer function: redundancy, polymorphism and questions remaining. Biol. Chem. 391, 873-879 (2010).
99. Heibein, J. A. et al. Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax. J. Exp. Med. 192, 1391-1402 (2000).
100. Sutton, V. R. et al. 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 (2000).
101. Sutton, V. R., Wowk, M. E., Cancilla, M. & Trapani, J. A. Caspase activation by granzyme B is indirect, and caspase autoprocessing requires the release of proapoptotic mitochondrial factors. Immunity 18, 319-329 (2003).
102. Kaiserman, D. et al. The major human and mouse granzymes are structurally and functionally divergent. J. Cell Biol. 175, 619-630 (2006).
103. Casciola-Rosen, L. et al. Mouse and human granzyme B have distinct tetrapeptide specificities and abilities to recruit the bid pathway. J. Biol. Chem. 282, 4545-4552 (2007).
104. Cullen, S. P., Adrain, C., Luthi, A. U., Duriez, P. J. & Martin, S. J. Human and murine granzyme B exhibit divergent substrate preferences. J. Cell Biol. 176, 435-444 (2007).
105. Thia, K. Y. & Trapani, J. A. The granzyme B gene is highly polymorphic in wild mice but essentially invariant in common inbred laboratory strains. Tissue Antigens 70, 198-204 (2007).
106. Andoniou, C. E. et al. A natural genetic variant of granzyme B confers lethality to a common viral infection. PLoS Pathog. 10, e1004526 (2014).
107. Mullbacher, A. et al. Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes. Proc. Natl Acad. Sci. USA 96, 13950-13955 (1999).
108. Susanto, O. et al. Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis. Cell Death Differ. 20, 1183-1193 (2013).
109. Metkar, S. S. et al. Human and mouse granzyme A induce a proinflammatory cytokine response. Immunity 29, 720-733 (2008).
110. Hoves, S. et al. A critical role for granzymes in antigen cross-presentation through regulating phagocytosis of killed tumor cells. J. Immunol. 187, 1166-1175 (2011).
111. Ewen, C. L., Kane, K. P. & Bleackley, R. C. Granzyme H induces cell death primarily via a Bcl-2-sensitive mitochondrial cell death pathway that does not require direct Bid activation. Mol. Immunol. 54, 309-318 (2013).
112. Poot, S. A. & Bovenschen, N. Granzyme M: behind enemy lines. Cell Death Differ. 21, 359-368 (2014).
113. Poot, S. A. et al. Granzyme M targets topoisomerase II? to trigger cell cycle arrest and caspase-dependent apoptosis. Cell Death Differ. 21, 416-426 (2014).
114. Pao, L. I. et al. Functional analysis of granzyme M and its role in immunity to infection. J. Immunol. 175, 3235-3243 (2005).
115. Andrade, F. Non-cytotoxic antiviral activities of granzymes in the context of the immune antiviral state. Immunol. Rev. 235, 128-146 (2010).
116. Joeckel, L. T. & Bird, P. I. Blessing or curse? Proteomics in granzyme research. Proteomics Clin. Appl. 8, 351-381 (2014).
117. Rawlings, N. D., Waller, M., Barrett, A. J. & Bateman, A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 42, D503-D509 (2014).
118. Brasacchio, D. et al. A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage. Cell Death Differ. 21, 748-760 (2014).
119. Irmler, M. et al. Granzyme A is an interleukin 1 ?-converting enzyme. J. Exp. Med. 181, 1917-1922 (1995).
120. Hiebert, P. R., Wu, D. & Granville, D. J. Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice. Cell Death Differ. 20, 1404-1414 (2013).
121. Zhong, C. et al. Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin ?1/? dimer of infected host cells. Cell Death Differ. 19, 882-890 (2012).
122. Bovenschen, N. et al. Elevated granzyme M-expressing lymphocytes during cytomegalovirus latency and reactivation after allogeneic stem cell transplantation. Clin. Immunol. 150, 1-11 (2014).
123. Van Domselaar, R. et al. Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication. Cell Death Differ. 20, 419-429 (2013).
124. Anthony, D. A. et al. A role for granzyme M in TLR4-driven inflammation and endotoxicosis. J. Immunol. 185, 1794-1803 (2010).
125. Afonina, I. S. et al. Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1?. Mol. Cell 44, 265-278 (2011).
126. Akeda, T. et al. CD8+ T cell granzyme B activates keratinocyte endogenous IL-18. Arch. Dermatol. Res. 306, 125-130 (2014).
127. Omoto, Y. et al. Granzyme Bisa novel interleukin-18 converting enzyme. J. Dermatol. Sci. 59, 129-135 (2010).
128. Wensink, A. C. et al. Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes. Proc. Natl Acad. Sci. USA 111, 5974-5979 (2014).
129. Arias, M. A. et al. Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis. Cell Rep. 8, 420-429 (2014).
130. Jenkins, M. R., Trapani, J. A., Doherty, P. C. & Turner, S. J. Granzyme K expressing cytotoxic T lymphocytes protects against influenza virus in granzyme AB?/? mice. Viral Immunol. 21, 341-346 (2008).
131. Marcet-Palacios, M. et al. Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3. PLoS Pathog. 7, e1002447 (2011).
132. van Domselaar, R., Quadir, R., van der Made, A. M., Broekhuizen, R. & Bovenschen, N. All human granzymes target hnRNP K that is essential for tumor cell viability. J. Biol. Chem. 287, 22854-22864 (2012).
133. Wang, S., Xia, P., Shi, L. & Fan, Z. 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 (2012).
134. De Poot, S. A., Lai, K. W., Hovingh, E. S. & Bovenschen, N. Granzyme M cannot induce cell death via cleavage of mouse FADD. Apoptosis 18, 533-534 (2013).
135. Baginska, J. et al. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl Acad. Sci. USA 110, 17450-17455 (2013).
136. Wang, S. et al. Rapid reuptake of granzyme B leads to emperitosis: an apoptotic cell-in-cell death of immune killer cells inside tumor cells. Cell Death Dis. 4, e856 (2013).
137. Sutton, V. R., Vaux, D. L. & Trapani, J. A. Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes. J. Immunol. 158, 5783-5790 (1997).
138. Sutton, V. R. et al. Granzyme B triggers a prolonged pressure to die in Bcl-2 overexpressing cells, defining a window of opportunity for effective treatment with ABT-737. Cell Death Dis. 3, e344 (2012).
139. Cote, M. et al. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J. Clin. Invest. 119, 3765-3773 (2009).
140. Jenkins, M. R. et al. Failed CTL/NK cell killing and cytokine hyper-secretion are directly linked through prolonged synapse time. J. Exp. Med. 212, 307-317 (2015).
141. Feldmann, J. et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115, 461-473 (2003).
142. zur Stadt, U. et al. 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 (2009).
143. zur Stadt, U. et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum. Mol. Genet. 14, 827-834 (2005).
144. Chia, J. et al. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc. Natl Acad. Sci. USA 106, 9809-9814 (2009).
145. van den Broek, M. E. et al. Decreased tumor surveillance in perforin-deficient mice. J. Exp. Med. 184, 1781-1790 (1996).
146. van den Broek, M. F., Kagi, D., Zinkernagel, R. M. & Hengartner, H. Perforin dependence of natural killer cell-mediated tumor control in vivo. Eur. J. Immunol. 25, 3514-3516 (1995).
147. Smyth, M. J. et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 192, 755-760 (2000).
148. Gatti, R. A. & Good, R. A. Occurrence of malignancy in immunodeficiency diseases. A literature review. Cancer 28, 89-98 (1971).
149. Katano, H. et al. Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood 103, 1244-1252 (2004).
150. Sekijima, Y. et al. The biological and chemical basis for tissue-selective amyloid disease. Cell 121, 73-85 (2005).
151. Wiseman, R. L., Powers, E. T., Buxbaum, J. N., Kelly, J. W. & Balch, W. E. An adaptable standard for protein export from the endoplasmic reticulum. Cell 131, 809-821 (2007).
152. Machaczka, M. et al. Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations. Haematologica 98, 760-764 (2013).
153. Meeths, M. et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 116, 2635-2643 (2010).
154. Pagel, J. et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood 119, 6016-6024 (2012).
155. Adami, J. et al. Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br. J. Cancer 89, 1221-1227 (2003).
156. Frisch, M., Biggar, R. J., Engels, E. A., Goedert, J. J. & AIDS-Cancer Match Registry Study Group. Association of cancer with AIDS-related immunosuppression in adults. JAMA 285, 1736-1745 (2001).
157. Grulich, A. E., van Leeuwen, M. T., Falster, M. O. & Vajdic, C. M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370, 59-67 (2007).
158. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734-1736 (1996).
159. Naidoo, J., Page, D. B. & Wolchok, J. D. Immune checkpoint blockade. Hematol. Oncol. Clin. North Am. 28, 585-600 (2014).
160. Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl Med. 6, 226ra32 (2014).
161. Voskoboinik, I. et al. Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood 110, 1184-1190 (2007).
162. House, I. G. et al. Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals. Immunol. Cell Biol. http://dx.doi.org/10.1038/icb.2015.1 (2015).
163. Mehta, P. A. et al. Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia 20, 1539-1541 (2006).
164. Trapani, J. A. et al. Human perforin mutations and susceptibility to multiple primary cancers. Oncoimmunology 2, e24185 (2013).
165. Zhang, K. et al. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood 124, 1331-1334 (2014).
166. Pena, S. V., Hanson, D. A., Carr, B. A., Goralski, T. J. & Krensky, A. M. Processing, subcellular localization, and function of 519 (granulysin), a human late T cell activation molecule with homology to small, lytic, granule proteins. J. Immunol. 158, 2680-2688 (1997).
167. Anderson, D. H. et al. Granulysin crystal structure and a structure-derived lytic mechanism. J. Mol. Biol. 325, 355-365 (2003).
168. Stenger, S. et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282, 121-125 (1998).
169. Walch, M. et al. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell 157, 1309-1323 (2014).
170. Chung, W. H. et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nature Med. 14, 1343-1350 (2008).
171. Bovenschen, N. et al. NK cell protease granzyme M targets ?-tubulin and disorganizes the microtubule network. J. Immunol. 180, 8184-8191 (2008).
172. Hu, D. et al. Cleavage of survivin by granzyme M triggers degradation of the survivin-X-linked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells. J. Biol. Chem. 285, 18326-18335 (2010).
173. Kelly, J. M. et al. Granzyme Mmediates a novel form of perforin-dependent cell death. J. Biol. Chem. 279, 22236-22242 (2004).
174. Lu, H. et al. Granzyme Mdirectly cleaves inhibitor of caspase-activated DNase (CAD) to unleash CAD leading to DNA fragmentation. J. Immunol. 177, 1171-1178 (2006).
175. Reboul, C. F., Whisstock, J. C. & Dunstone, M. A. A new model for pore formation by cholesterol-dependent cytolysins. PLoS Comput. Biol. 10, e1003791 (2014).
176. Sedelies, K. A. et al. Discordant regulation of granzyme H and granzyme B expression in human lymphocytes. J. Biol. Chem. 279, 26581-26587 (2004).
177. Busiello, R. et al. Atypical features of familial hemophagocytic lymphohistiocytosis. Blood 103, 4610-4612 (2004).
178. Cannella, S. et al. Germline mutations of the perforin gene are a frequent occurrence in childhood anaplastic large cell lymphoma. Cancer 109, 2566-2571 (2007).
179. Clementi, R. et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 100, 2266-2267 (2002).
180. Clementi, R. et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood 105, 4424-4428 (2005).
181. Feldmann, J. et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br. J. Haematol. 117, 965-972 (2002).
182. Mancebo, E. et al. Familial hemophagocytic lymphohistiocytosis in an adult patient homozygous for A91V in the perforin gene, with tuberculosis infection. Haematologica 91, 1257-1260 (2006).
183. Marcenaro, S. et al. 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 (2006).
184. Okur, H. et al. Clinical and molecular aspects of Turkish familial hemophagocytic lymphohistiocytosis patients with perforin mutations. Leuk. Res. 32, 972-975 (2008).
185. Risma, K. A., Frayer, R. W., Filipovich, A. H. & Sumegi, J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J. Clin. Invest. 116, 182-192 (2006).
186. Santoro, A. et al. A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica 90, 697-698 (2005).
187. Trambas, C. et al. A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. Blood 106, 932-937 (2005).
188. Trizzino, A. et al. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations. J. Med. Genet. 45, 15-21 (2008).
189. Orange, J. S. et al. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc. Natl Acad. Sci. USA 99, 11351-11356 (2002).