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Perforin: A Key Pore-Forming Protein for Immune Control of Viruses and Cancer

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MACPF/CDC Proteins - Agents of Defence, Attack and Invasion

Part of the book series: Subcellular Biochemistry ((SCBI,volume 80))

Abstract

Perforin (PFN) is the key pore-forming molecule in the cytotoxic granules of immune killer cells. Expressed only in killer cells, PFN is the rate-limiting molecule for cytotoxic function, delivering the death-inducing granule serine proteases (granzymes) into target cells marked for immune elimination. In this chapter we describe our current understanding of how PFN accomplishes this task. We discuss where PFN is expressed and how its expression is regulated, the biogenesis and storage of PFN in killer cells and how they are protected from potential damage, how it is released, how it delivers Granzymes into target cells and the consequences of PFN deficiency.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

APC:

Antigen presenting cells

ASM:

Acid sphingomyelinase

CDCs:

Cholesterol-dependent cytolysins

CI-MPR:

Cation-independent mannose-6-phosphate receptor

c-SMAC:

The central region of the immune synapse

CTL:

Cytotoxic T lymphocytes

EOMES :

Eomesodermin

ER:

Endoplasmic reticulum

FHL:

Familial hemophagocytic lymphohistiocytosis

GNLY:

Granulysin

Gzm:

Granzymes

GvHD:

Graft-versus-host disease

HGH:

Hemophagocytic lymphohistiocytosis

IL2:

Interleukin-2

IS:

Immune synapse

LCMV:

Lymphochoriomeningitis virus

LCR:

Locus control region

MAC:

Membrane attack complex

MACPF:

Membrane attack complex/perforin

MTOC:

Microtubule organizing center

NK:

Natural killer

PFN:

Perforin

SLO:

Streptolysin O

SNARE:

Soluble N-ethylmaleimide-sensitive factor accessory protein receptor

TCR:

T cell receptor

References

  1. Araki Y, Fann M, Wersto R, Weng NP (2008) Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B). J Immunol 180:8102–8108

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Araki Y, Wang Z, Zang C, Wood WH 3rd, Schones D, Cui K, Roh TY, Lhotsky B, Wersto RP, Peng W, Becker KG, Zhao K, Weng NP (2009) Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T cells. Immunity 30:912–925

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Badovinac VP, Hamilton SE, Harty JT (2003) Viral infection results in massive CD8+ T cell expansion and mortality in vaccinated perforin-deficient mice. Immunity 18:463–474

    CAS  PubMed  Google Scholar 

  4. Balaji KN, Schaschke N, Machleidt W, Catalfamo M, Henkart PA (2002) Surface cathepsin B protects cytotoxic lymphocytes from self-destruction after degranulation. J Exp Med 196:493–503

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Banerjee A, Gordon SM, Intlekofer AM, Paley MA, Mooney EC, Lindsten T, Wherry EJ, Reiner SL (2010) Cutting edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J Immunol 185:4988–4992

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Baran K, Ciccone A, Peters C, Yagita H, Bird PI, Villadangos JA, Trapani JA (2006) 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

    CAS  PubMed  Google Scholar 

  7. Baran K, Dunstone M, Chia J, Ciccone A, Browne KA, Clarke CJ, Lukoyanova N, Saibil H, Whisstock JC, Voskoboinik I, Trapani JA (2009) The molecular basis for perforin oligomerization and transmembrane pore assembly. Immunity 30:684–695

    CAS  PubMed  Google Scholar 

  8. Bird CH, Sun J, Ung K, Karambalis D, Whisstock JC, Trapani JA, Bird PI (2005) Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells. Mol Cell Biol 25:7854–7867

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Bischofberger M, Gonzalez MR, van der Goot FG (2009) Membrane injury by pore-forming proteins. Curr Opin Cell Biol 21:589–595

    CAS  PubMed  Google Scholar 

  10. Bossi G, Booth S, Clark R, Davis EG, Liesner R, Richards K, Starcevic M, Stinchcombe J, Trambas C, Dell’Angelica EC, Griffiths GM (2005) Normal lytic granule secretion by cytotoxic T lymphocytes deficient in BLOC-1, -2 and -3 and myosins Va, VIIa and XV. Traffic 6:243–251

    CAS  PubMed  Google Scholar 

  11. Brennan AJ, Chia J, Browne KA, Ciccone A, Ellis S, Lopez JA, Susanto O, Verschoor S, Yagita H, Whisstock JC, Trapani JA, Voskoboinik I (2011) Protection from endogenous perforin: glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes. Immunity 34:879–892

    CAS  PubMed  Google Scholar 

  12. Brown DM, Dilzer AM, Meents DL, Swain SL (2006) CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol 177:2888–2898

    CAS  PubMed  Google Scholar 

  13. Brown DM, Kamperschroer C, Dilzer AM, Roberts DM, Swain SL (2009) IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity in antigen specific CD4 + T cells. Cell Immunol 257:69–79

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Browne KA, Blink E, Sutton VR, Froelich CJ, Jans DA, Trapani JA (1999) 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

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Cannella S, Santoro A, Bruno G, Pillon M, Mussolin L, Mangili G, Rosolen A, Arico M (2007) Germline mutations of the perforin gene are a frequent occurrence in childhood anaplastic large cell lymphoma. Cancer 109:2566–2571

    CAS  PubMed  Google Scholar 

  16. Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I (2009) 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

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Cho OH, Shin HM, Miele L, Golde TE, Fauq A, Minter LM, Osborne BA (2009) Notch regulates cytolytic effector function in CD8+ T cells. J Immunol 182:3380–3389

    CAS  PubMed  Google Scholar 

  18. Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, Groner Y, Rao A (2009) Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med 206:51–59

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Cui W, Kaech SM (2010) Generation of effector CD8+ T cells and their conversion to memory T cells. Immunol Rev 236:151–166

    CAS  PubMed  Google Scholar 

  20. de Saint Basile G, Menasche G, Fischer A (2010) Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 10:568–579

    PubMed  Google Scholar 

  21. Dupuis M, Schaerer E, Krause KH, Tschopp J (1993) The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. J Exp Med 177:1–7

    CAS  PubMed  Google Scholar 

  22. Dustin ML (2009) The cellular context of T cell signaling. Immunity 30:482–492

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Dustin ML, Long EO (2010) Cytotoxic immunological synapses. Immunol Rev 235:24–34

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Fann M, Godlove JM, Catalfamo M, Wood WH 3rd, Chrest FJ, Chun N, Granger L, Wersto R, Madara K, Becker K, Henkart PA, Weng NP (2006) Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8(+) T-cell response. Blood 108:3363–3370

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Farrand AJ, LaChapelle S, Hotze EM, Johnson AE, Tweten RK (2010) Only two amino acids are essential for cytolytic toxin recognition of cholesterol at the membrane surface. Proc Natl Acad Sci USA 107:4341–4346

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, Ley TJ (2007) Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26:798–811

    CAS  PubMed  Google Scholar 

  27. Fraser SA, Karimi R, Michalak M, Hudig D (2000) Perforin lytic activity is controlled by calreticulin. J Immunol 164:4150–4155

    CAS  PubMed  Google Scholar 

  28. Froelich CJ, Orth K, Turbov J, Seth P, Gottlieb R, Babior B, Shah GM, Bleackley RC, Dixit VM, Hanna W (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

    CAS  PubMed  Google Scholar 

  29. Galvin JP, Spaeny-Dekking LH, Wang B, Seth P, Hack CE, Froelich CJ (1999) Apoptosis induced by granzyme B-glycosaminoglycan complexes: implications for granule-mediated apoptosis in vivo. J Immunol 162:5345–5350

    CAS  PubMed  Google Scholar 

  30. Gilbert RJ, Mikelj M, Dalla Serra M, Froelich CJ, Anderluh G (2013) Effects of MACPF/CDC proteins on lipid membranes. Cell Mol Life Sci 70:2083–2098

    CAS  PubMed  Google Scholar 

  31. Glimcher LH, Townsend MJ, Sullivan BM, Lord GM (2004) Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol 4:900–911

    CAS  PubMed  Google Scholar 

  32. Graubert TA, Russell JH, Ley TJ (1996) The role of granzyme B in murine models of acute graft-versus-host disease and graft rejection. Blood 87:1232–1237

    CAS  PubMed  Google Scholar 

  33. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601

    CAS  PubMed  Google Scholar 

  34. Grujic M, Braga T, Lukinius A, Eloranta ML, Knight SD, Pejler G, Abrink M (2005) Serglycin-deficient cytotoxic T lymphocytes display defective secretory granule maturation and granzyme B storage. J Biol Chem 280:33411–33418

    CAS  PubMed  Google Scholar 

  35. Gupta M, Greer P, Mahanty S, Shieh WJ, Zaki SR, Ahmed R, Rollin PE (2005) CD8-mediated protection against Ebola virus infection is perforin dependent. J Immunol 174:4198–4202

    CAS  PubMed  Google Scholar 

  36. Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, van Lier RA (1997) Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 186:1407–1418

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Herz J, Pardo J, Kashkar H, Schramm M, Kuzmenkina E, Bos E, Wiegmann K, Wallich R, Peters PJ, Herzig S, Schmelzer E, Kronke M, Simon MM, Utermohlen O (2009) Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat Immunol 10:761–768

    CAS  PubMed  Google Scholar 

  38. Holopainen JM, Angelova MI, Kinnunen PK (2000) Vectorial budding of vesicles by asymmetrical enzymatic formation of ceramide in giant liposomes. Biophys J 78:830–838

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW (2008) Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. J Cell Biol 180:905–914

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Intlekofer AM, Banerjee A, Takemoto N, Gordon SM, Dejong CS, Shin H, Hunter CA, Wherry EJ, Lindsten T, Reiner SL (2008) Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321:408–411

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Jordan MB, Hildeman D, Kappler J, Marrack P (2004) An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 104:735–743

    CAS  PubMed  Google Scholar 

  42. Kagi D, Ledermann B, Burki K, Hengartner H, Zinkernagel RM (1994) CD8+ T cell-mediated protection against an intracellular bacterium by perforin-dependent cytotoxicity. Eur J Immunol 24:3068–3072

    CAS  PubMed  Google Scholar 

  43. Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37

    CAS  PubMed  Google Scholar 

  44. Kataoka T, Togashi K, Takayama H, Takaku K, Nagai K (1997) Inactivation and proteolytic degradation of perforin within lytic granules upon neutralization of acidic pH. Immunology 91:493–500

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Keefe D, Shi L, Feske S, Massol R, Navarro F, Kirchhausen T, Lieberman J (2005) Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity 23:249–262

    CAS  PubMed  Google Scholar 

  46. Krzewski K, Coligan JE (2012) Human NK cell lytic granules and regulation of their exocytosis. Front Immunol 3:335

    PubMed Central  PubMed  Google Scholar 

  47. Kurschus FC, Bruno R, Fellows E, Falk CS, Jenne DE (2005) Membrane receptors are not required to deliver granzyme B during killer cell attack. Blood 105:2049–2058

    CAS  PubMed  Google Scholar 

  48. Law RH, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, Dunstone MA, D’Angelo ME, Orlova EV, Coulibaly F, Verschoor S, Browne KA, Ciccone A, Kuiper MJ, Bird PI, Trapani JA, Saibil HR, Whisstock JC (2010) The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468:447–451

    CAS  PubMed  Google Scholar 

  49. Lichtenheld MG, Olsen KJ, Lu P, Lowrey DM, Hameed A, Hengartner H, Podack ER (1988) Structure and function of human perforin. Nature 335:448–451

    CAS  PubMed  Google Scholar 

  50. Lichtenheld MG, Podack ER (1992) Structure and function of the murine perforin promoter and upstream region. Reciprocal gene activation or silencing in perforin positive and negative cells. J Immunol 149:2619–2626

    CAS  PubMed  Google Scholar 

  51. Liu D, Bryceson YT, Meckel T, Vasiliver-Shamis G, Dustin ML, Long EO (2009) Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity 31:99–109

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Lopez JA, Susanto O, Jenkins MR, Lukoyanova N, Sutton VR, Law RH, Johnston A, Bird CH, Bird PI, Whisstock JC, Trapani JA, Saibil HR, Voskoboinik I (2013) Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood 121:2659–2668

    CAS  PubMed  Google Scholar 

  53. Masson D, Peters PJ, Geuze HJ, Borst J, Tschopp J (1990) Interaction of chondroitin sulfate with perforin and granzymes of cytolytic T-cells is dependent on pH. Biochemistry 29:11229–11235

    CAS  PubMed  Google Scholar 

  54. McCormack R, de Armas LR, Shiratsuchi M, Ramos JE, Podack ER (2013) Inhibition of intracellular bacterial replication in fibroblasts is dependent on the perforin-like protein (perforin-2) encoded by macrophage-expressed gene 1. J Innate Immun 5:185–194

    CAS  PubMed Central  PubMed  Google Scholar 

  55. McNeil PL, Kirchhausen T (2005) An emergency response team for membrane repair. Nat Rev Mol Cell Biol 6:499–505

    CAS  PubMed  Google Scholar 

  56. Mehta PA, Davies SM, Kumar A, Devidas M, Lee S, Zamzow T, Elliott J, Villanueva J, Pullen J, Zewge Y, Filipovich A (2006) Perforin polymorphism A91 V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Leukemia 20:1539–1541

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Metkar SS, Wang B, Aguilar-Santelises M, Raja SM, Uhlin-Hansen L, Podack E, Trapani JA, Froelich CJ (2002) Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 16:417–428

    CAS  PubMed  Google Scholar 

  58. Metkar SS, Wang B, Catalan E, Anderluh G, Gilbert RJ, Pardo J, Froelich CJ (2011) Perforin rapidly induces plasma membrane phospholipid flip-flop. PLoS ONE 6:e24286

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Millard PJ, Henkart MP, Reynolds CW, Henkart PA (1984) Purification and properties of cytoplasmic granules from cytotoxic rat LGL tumors. J Immunol 132:3197–3204

    CAS  PubMed  Google Scholar 

  60. Motyka B, Korbutt G, Pinkoski MJ, Heibein JA, Caputo A, Hobman M, Barry M, Shostak I, Sawchuk T, Holmes CF, Gauldie J, Bleackley RC (2000) Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 103:491–500

    CAS  PubMed  Google Scholar 

  61. Mullbacher A, Ebnet K, Blanden RV, Hla RT, Stehle T, Museteanu C, Simon MM (1996) Granzyme A is critical for recovery of mice from infection with the natural cytopathic viral pathogen, ectromelia. Proc Natl Acad Sci USA 93:5783–5787

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Northrop JK, Wells AD, Shen H (2008) Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J Immunol 181:865–868

    CAS  PubMed  Google Scholar 

  63. Ohkawa T, Seki S, Dobashi H, Koike Y, Habu Y, Ami K, Hiraide H, Sekine I (2001) Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells. Immunology 103:281–290

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Orange JS (2007) The lytic NK cell immunological synapse and sequential steps in its formation. Adv Exp Med Biol 601:225–233

    PubMed  Google Scholar 

  65. Pachlopnik Schmid J, Cote M, Menager MM, Burgess A, Nehme N, Menasche G, Fischer A, de Saint Basile G (2010) Inherited defects in lymphocyte cytotoxic activity. Immunol Rev 235:10–23

    Google Scholar 

  66. Pachlopnik Schmid J, Ho CH, Chretien F, Lefebvre JM, Pivert G, Kosco-Vilbois M, Ferlin W, Geissmann F, Fischer A, de Saint Basile G (2009) Neutralization of IFNgamma defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice. EMBO Mol Med 1:112–124

    Google Scholar 

  67. Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, Banica M, DiCioccio CB, Gross DA, Mao CA, Shen H, Cereb N, Yang SY, Lindsten T, Rossant J, Hunter CA, Reiner SL (2003) Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302:1041–1043

    CAS  PubMed  Google Scholar 

  68. Peters PJ, Borst J, Oorschot V, Fukuda M, Krahenbuhl O, Tschopp J, Slot JW, Geuze HJ (1991) Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med 173:1099–1109

    CAS  PubMed  Google Scholar 

  69. Pipkin ME, Ljutic B, Cruz-Guilloty F, Nouzova M, Rao A, Zuniga-Pflucker JC, Lichtenheld MG (2007) Chromosome transfer activates and delineates a locus control region for perforin. Immunity 26:29–41

    CAS  PubMed  Google Scholar 

  70. Pipkin ME, Rao A, Lichtenheld MG (2010) The transcriptional control of the perforin locus. Immunol Rev 235:55–72

    CAS  PubMed  Google Scholar 

  71. Podack ER, Young JD, Cohn ZA (1985) Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules. Proc Natl Acad Sci USA 82:8629–8633

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Praper T, Sonnen A, Viero G, Kladnik A, Froelich CJ, Anderluh G, Dalla Serra M, Gilbert RJ (2011) Human perforin employs different avenues to damage membranes. J Biol Chem 286:2946–2955

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Praper T, Sonnen AF, Kladnik A, Andrighetti AO, Viero G, Morris KJ, Volpi E, Lunelli L, Dalla Serra M, Froelich CJ, Gilbert RJ, Anderluh G (2011) Perforin activity at membranes leads to invaginations and vesicle formation. Proc Natl Acad Sci USA 108:21016–21021

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Ramachandran R, Heuck AP, Tweten RK, Johnson AE (2002) Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin. Nat Struct Biol 9:823–827

    CAS  PubMed  Google Scholar 

  75. Ramachandran R, Tweten RK, Johnson AE (2004) Membrane-dependent conformational changes initiate cholesterol-dependent cytolysin oligomerization and intersubunit beta-strand alignment. Nat Struct Mol Biol 11:697–705

    CAS  PubMed  Google Scholar 

  76. Reddy A, Caler EV, Andrews NW (2001) Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell 106:157–169

    CAS  PubMed  Google Scholar 

  77. Rosado CJ, Buckle AM, Law RH, Butcher RE, Kan WT, Bird CH, Ung K, Browne KA, Baran K, Bashtannyk-Puhalovich TA, Faux NG, Wong W, Porter CJ, Pike RN, Ellisdon AM, Pearce MC, Bottomley SP, Emsley J, Smith AI, Rossjohn J, Hartland EL, Voskoboinik I, Trapani JA, Bird PI, Dunstone MA, Whisstock JC (2007) A common fold mediates vertebrate defense and bacterial attack. Science 317:1548–1551

    CAS  PubMed  Google Scholar 

  78. Rutishauser RL, Kaech SM (2010) Generating diversity: transcriptional regulation of effector and memory CD8 T-cell differentiation. Immunol Rev 235:219–233

    CAS  PubMed  Google Scholar 

  79. Salcedo TW, Azzoni L, Wolf SF, Perussia B (1993) Modulation of perforin and granzyme messenger RNA expression in human natural killer cells. J Immunol 151:2511–2520

    CAS  PubMed  Google Scholar 

  80. Santoro A, Cannella S, Trizzino A, Lo Nigro L, Corsello G, Arico M (2005) A single amino acid change A91 V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica 90:697–698

    PubMed  Google Scholar 

  81. Sauer H, Pratsch L, Tschopp J, Bhakdi S, Peters R (1991) Functional size of complement and perforin pores compared by confocal laser scanning microscopy and fluorescence microphotolysis. Biochim Biophys Acta 1063:137–146

    CAS  PubMed  Google Scholar 

  82. Schreiber TH, Podack ER (2009) A critical analysis of the tumour immunosurveillance controversy for 3-MCA-induced sarcomas. Br J Cancer 101:381–386

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Shepard LA, Heuck AP, Hamman BD, Rossjohn J, Parker MW, Ryan KR, Johnson AE, Tweten RK (1998) Identification of a membrane-spanning domain of the thiol-activated pore-forming toxin Clostridium perfringens perfringolysin O: an alpha-helical to beta-sheet transition identified by fluorescence spectroscopy. Biochemistry 37:14563–14574

    CAS  PubMed  Google Scholar 

  84. Shi L, Keefe D, Durand E, Feng H, Zhang D, Lieberman J (2005) Granzyme B binds to target cells mostly by charge and must be added at the same time as perforin to trigger apoptosis. J Immunol 174:5456–5461

    CAS  PubMed  Google Scholar 

  85. Shi L, Mai S, Israels S, Browne K, Trapani JA, Greenberg AH (1997) Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization. J Exp Med 185:855–866

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Shinkai Y, Takio K, Okumura K (1988) Homology of perforin to the ninth component of complement (C9). Nature 334:525–527

    CAS  PubMed  Google Scholar 

  87. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA (2000) Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 192:755–760

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint Basile G, Kumar V (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957–1959

    Google Scholar 

  89. Street SE, Zerafa N, Iezzi M, Westwood JA, Stagg J, Musiani P, Smyth MJ (2007) Host perforin reduces tumor number but does not increase survival in oncogene-driven mammary adenocarcinoma. Cancer Res 67:5454–5460

    CAS  PubMed  Google Scholar 

  90. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669

    CAS  PubMed  Google Scholar 

  91. Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, Schuchman E, Tabas I, Andrews NW (2010) Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J Cell Biol 189:1027–1038

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Terasaki M, Miyake K, McNeil PL (1997) Large plasma membrane disruptions are rapidly resealed by Ca2+-dependent vesicle-vesicle fusion events. J Cell Biol 139:63–74

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Thiery J, Keefe D, Boulant S, Boucrot E, Walch M, Martinvalet D, Goping IS, Bleackley RC, Kirchhausen T, Lieberman J (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

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Thiery J, Keefe D, Saffarian S, Martinvalet D, Walch M, Boucrot E, Kirchhausen T, Lieberman J (2010) 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

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Trambas C, Gallo F, Pende D, Marcenaro S, Moretta L, De Fusco C, Santoro A, Notarangelo L, Arico M, Griffiths GM (2005) A single amino acid change, A91 V, leads to conformational changes that can impair processing to the active form of perforin. Blood 106:932–937

    CAS  PubMed  Google Scholar 

  96. Trapani JA, Sutton VR, Thia KY, Li YQ, Froelich CJ, Jans DA, Sandrin MS, Browne KA (2003) A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. J Cell Biol 160:223–233

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Trimble LA, Lieberman J (1998) Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 zeta, the signaling chain of the T-cell receptor complex. Blood 91:585–594

    CAS  PubMed  Google Scholar 

  98. Tschopp J, Masson D, Stanley KK (1986) Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis. Nature 322:831–834

    CAS  PubMed  Google Scholar 

  99. Uellner R, Zvelebil MJ, Hopkins J, Jones J, MacDougall LK, Morgan BP, Podack E, Waterfield MD, Griffiths GM (1997) Perforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipid-binding C2 domain. EMBO J 16:7287–7296

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Vivier E, Sorrell JM, Ackerly M, Robertson MJ, Rasmussen RA, Levine H, Anderson P (1993) Developmental regulation of a mucinlike glycoprotein selectively expressed on natural killer cells. J Exp Med 178:2023–2033

    CAS  PubMed  Google Scholar 

  101. Voskoboinik I, Dunstone MA, Baran K, Whisstock JC, Trapani JA (2010) Perforin: structure, function, and role in human immunopathology. Immunol Rev 235:35–54

    CAS  PubMed  Google Scholar 

  102. Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6:940–952

    CAS  PubMed  Google Scholar 

  103. Voskoboinik I, Sutton VR, Ciccone A, House CM, Chia J, Darcy PK, Yagita H, Trapani JA (2007) Perforin activity and immune homeostasis: the common A91 V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood 110:1184–1190

    CAS  PubMed  Google Scholar 

  104. Voskoboinik I, Thia MC, De Bono A, Browne K, Cretney E, Jackson JT, Darcy PK, Jane SM, Smyth MJ, Trapani JA (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

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Voskoboinik I, Thia MC, Fletcher J, Ciccone A, Browne K, Smyth MJ, Trapani JA (2005) 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

    CAS  PubMed  Google Scholar 

  106. Walsh CM, Matloubian M, Liu CC, Ueda R, Kurahara CG, Christensen JL, Huang MT, Young JD, Ahmed R, Clark WR (1994) Immune function in mice lacking the perforin gene. Proc Natl Acad Sci USA 91:10854–10858

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Werneck MB, Lugo-Villarino G, Hwang ES, Cantor H, Glimcher LH (2008) T-bet plays a key role in NK-mediated control of melanoma metastatic disease. J Immunol 180:8004–8010

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12:492–499

    CAS  PubMed  Google Scholar 

  109. Yamamoto K, Shibata F, Miyasaka N, Miura O (2002) The human perforin gene is a direct target of STAT4 activated by IL-12 in NK cells. Biochem Biophys Res Commun 297:1245–1252

    CAS  PubMed  Google Scholar 

  110. Youn BS, Kim KK, Kwon BS (1996) A critical role of Sp1- and Ets-related transcription factors in maintaining CTL-specific expression of the mouse perforin gene. J Immunol 157:3499–3509

    CAS  PubMed  Google Scholar 

  111. Yu CR, Ortaldo JR, Curiel RE, Young HA, Anderson SK, Gosselin P (1999) Role of a STAT binding site in the regulation of the human perforin promoter. J Immunol 162:2785–2790

    CAS  PubMed  Google Scholar 

  112. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188:2205–2213

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Zediak VP, Wherry EJ, Berger SL (2011) The contribution of epigenetic memory to immunologic memory. Curr Opin Genet Dev 21:154–159

    CAS  PubMed  Google Scholar 

  114. Zhang J, Scordi I, Smyth MJ, Lichtenheld MG (1999) Interleukin 2 receptor signaling regulates the perforin gene through signal transducer and activator of transcription (Stat)5 activation of two enhancers. J Exp Med 190:1297–1308

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Zhang Y, Lichtenheld MG (1997) Non-killer cell-specific transcription factors silence the perforin promoter. J Immunol 158:1734–1741

    CAS  PubMed  Google Scholar 

  116. Zhou J, Zhang J, Lichtenheld MG, Meadows GG (2002) A role for NF-kappa B activation in perforin expression of NK cells upon IL-2 receptor signaling. J Immunol 169:1319–1325

    CAS  PubMed  Google Scholar 

  117. Zhu Y, Ju S, Chen E, Dai S, Li C, Morel P, Liu L, Zhang X, Lu B (2010) T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. J Immunol 185:3174–3183

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. INSERM U753, University Paris Sud and Gustave Roussy Cancer Campus, Villejuif, France

    Jerome Thiery

  2. Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Judy Lieberman

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  1. Jerome Thiery
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  2. Judy Lieberman
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Correspondence to Judy Lieberman .

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  1. National Institute of Chemistry, Ljubljana, Slovenia, Laboratory for Molecular Biology and Nanobiotechnology, Ljubljana, Slovenia

    Gregor Anderluh

  2. Division of Structural Biology, University of Oxford Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

    Robert Gilbert

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Thiery, J., Lieberman, J. (2014). Perforin: A Key Pore-Forming Protein for Immune Control of Viruses and Cancer. In: Anderluh, G., Gilbert, R. (eds) MACPF/CDC Proteins - Agents of Defence, Attack and Invasion. Subcellular Biochemistry, vol 80. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8881-6_10

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