Perforin: structure and function.

Perforin is a cytolytic mediator produced by killer lymphocytes, and is stored in and released by cytoplasmic granules. The protein is partially homologous to the terminal components of the membrane attack complex of complement and produces pores of up to 20 nm in diameter on target membranes. Its genomic and protein structures have recently been unraveled, and its function elucidated through the availability of genetically engineered, perforin-deficient mice. Here Chau-Ching Liu, Craig M. Walsh and John Ding-E Young briefly outline certain biochemical and molecular features of perforin, and discuss the still-evolving issues concerning the relevance of perforin and Fas in cell killing.

[1]  D. Schmid,et al.  A comparison of lysis mediated by Lyt 2+ TNP-specific cytotoxic-T-lymphocyte (CTL) lines with that mediated by rapidly internalized lymphotoxin-containing supernatant fluids: evidence for a role of soluble mediators in CTL-mediated killing. , 1985, Cellular immunology.

[2]  S. Rafii,et al.  Perforin and serine esterase gene expression in stimulated human T cells. Kinetics, mitogen requirements, and effects of cyclosporin A , 1989, The Journal of experimental medicine.

[3]  J. Tschopp,et al.  Isolation of a lytic, pore-forming protein (perforin) from cytolytic T-lymphocytes. , 1985, The Journal of biological chemistry.

[4]  M. Peitsch,et al.  Phosphorylcholine acts as a Ca2+-dependent receptor molecule for lymphocyte perforin , 1989, Nature.

[5]  C. Hsieh,et al.  Mechanisms of lysis by cytotoxic T lymphocyte clones. Lytic activity and gene expression in cloned antigen-specific CD4+ and CD8+ T lymphocytes. , 1991, Journal of immunology.

[6]  J. Dankert,et al.  Recovery of human neutrophils from complement attack: removal of the membrane attack complex by endocytosis and exocytosis. , 1987, Journal of immunology.

[7]  P. Möller,et al.  Monoclonal antibody-mediated tumor regression by induction of apoptosis. , 1989, Science.

[8]  J. D. Young,et al.  A calcium- and perforin-independent pathway of killing mediated by murine cytolytic lymphocytes , 1987, The Journal of experimental medicine.

[9]  P. Golstein,et al.  Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity , 1993, The Journal of experimental medicine.

[10]  L. Azzoni,et al.  Modulation of perforin and granzyme messenger RNA expression in human natural killer cells. , 1993, Journal of immunology.

[11]  J. D. Young,et al.  Purified perforin induces target cell lysis but not DNA fragmentation , 1989, The Journal of experimental medicine.

[12]  E. Podack,et al.  A central role of perforin in cytolysis? , 1991, Annual review of immunology.

[13]  H Hengartner,et al.  Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. , 1994, Science.

[14]  K. Nagashima,et al.  Direct evidence for release of pore‐forming protein during NK cellular lysis , 1992, Journal of leukocyte biology.

[15]  J. Slot,et al.  Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes , 1991, The Journal of experimental medicine.

[16]  E. Podack,et al.  Perforin expression in human peripheral blood mononuclear cells. Definition of an IL-2-independent pathway of perforin induction in CD8+ T cells. , 1992, Journal of immunology.

[17]  E. Podack,et al.  Regulation of perforin gene expression in a T cell hybrid with inducible cytolytic activity , 1993, European journal of immunology.

[18]  B. Bonavida,et al.  Studies on the mechanism of natural killer cell-mediated cytotoxicity. VII. functional comparison of human natural killer cytotoxic factors with recombinant lymphotoxin and tumor necrosis factor. , 1987, Journal of immunology.

[19]  J. D. Young,et al.  Granulated lymphoid cells of the pregnant uterus: morphological and functional features. , 1994, International review of cytology.

[20]  B. Kwon,et al.  Structure of the mouse pore-forming protein (perforin) gene: analysis of transcription initiation site, 5' flanking sequence, and alternative splicing of 5' untranslated regions , 1991, The Journal of experimental medicine.

[21]  E. Podack,et al.  Assembly of two types of tubules with putative cytolytic function by cloned natural killer cells , 1983, Nature.

[22]  E. Podack,et al.  Structure of the human perforin gene. A simple gene organization with interesting potential regulatory sequences. , 1989, Journal of immunology.

[23]  J. Tschopp,et al.  Granzymes: a family of serine proteases in granules of cytolytic T lymphocytes. , 1989, Current topics in microbiology and immunology.

[24]  P. Henkart,et al.  Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A , 1989, The Journal of experimental medicine.

[25]  J. Young,et al.  Channel-forming activity of the perforin N-terminus and a putative alpha-helical region homologous with complement C9. , 1992, Biochemistry.

[26]  Y. Shinkai,et al.  Role of perforin in lymphocyte-mediated cytolysis. , 1992, Advances in immunology.

[27]  S. Singer,et al.  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 , 1986, The Journal of experimental medicine.

[28]  Y. Shinkai,et al.  Homology of perforin to the ninth component of complement (C9) , 1988, Nature.

[29]  J. Shiver,et al.  Cytotoxicity with target DNA breakdown by rat basophilic leukemia cells expressing both cytolysin and granzyme A , 1992, Cell.

[30]  J. D. Young,et al.  Multiple mechanisms of lymphocyte-mediated killing. , 1988, Immunology today.

[31]  R. Hornung,et al.  Target cell DNA fragmentation is mediated by lymphotoxin and tumor necrosis factor. , 1987, Lymphokine research.

[32]  M. Peitsch,et al.  Localization and molecular modelling of the membrane-inserted domain of the ninth component of human complement and perforin. , 1990, Molecular immunology.

[33]  E. Podack,et al.  Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity , 1986, Cell.

[34]  Hans Hengartner,et al.  Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice , 1994, Nature.

[35]  Y. Shinkai,et al.  Expression of perforin and cytolytic potential of human peripheral blood lymphocyte subpopulations. , 1992, International immunology.

[36]  Paul Anderson,et al.  A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells , 1991, Cell.

[37]  J. Tschopp,et al.  Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis , 1986, Nature.

[38]  C. Helgason,et al.  Peritoneal exudate lymphocyte and mixed lymphocyte culture hybridomas are cytolytic in the absence of cytotoxic cell proteinases and perforin , 1992, European journal of immunology.

[39]  H. Young,et al.  IL-2 and IL-6 synergize to augment the pore-forming protein gene expression and cytotoxic potential of human peripheral blood T cells. , 1990, Journal of immunology.

[40]  R. Aebersold,et al.  Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions , 1992, The Journal of experimental medicine.

[41]  P. Henkart.  Mechanism of lymphocyte-mediated cytotoxicity. , 1985, Annual review of immunology.

[42]  V. Engelhard,et al.  Reorientation and fusion of cytotoxic T lymphocyte granules after interaction with target cells as determined by high resolution cinemicrography. , 1986, Journal of immunology.

[43]  E. Podack,et al.  Structure and function of the murine perforin promoter and upstream region. Reciprocal gene activation or silencing in perforin positive and negative cells. , 1992, Journal of immunology.

[44]  Atsushi Hase,et al.  The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis , 1991, Cell.

[45]  N. Jenkins,et al.  Generalized lymphoproliferative disease in mice, caused by a point mutation in the fas ligand , 1994, Cell.

[46]  J. Tschopp,et al.  Inhibition of lymphocyte mediated cytotoxicity by perforin antisense oligonucleotides. , 1990, The EMBO journal.

[47]  B. Kwon,et al.  Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10. Similarities to and differences from C9 , 1990, The Journal of experimental medicine.

[48]  Takashi Suda,et al.  Molecular cloning and expression of the fas ligand, a novel member of the tumor necrosis factor family , 1993, Cell.

[49]  M. Sitkovsky,et al.  Exocytosis of cytolytic granules may not be required for target cell lysis by cytotoxic T-lymphocytes , 1987, Nature.

[50]  G. Berke.  The binding and lysis of target cells by cytotoxic lymphocytes: molecular and cellular aspects. , 1994, Annual review of immunology.

[51]  S. Rafii,et al.  How lymphocytes kill. , 1990, Annual Review of Medicine.

[52]  G. Berke,et al.  Mechanism of lymphocyte-mediated cytolysis: functional cytolytic T cells lacking perforin and granzymes. , 1993, Immunology.

[53]  H. Young,et al.  Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-beta. , 1991, Journal of immunology.

[54]  P. Lu,et al.  Structure and function of human perforin , 1988, Nature.

[55]  K. Okumura,et al.  Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. , 1994, Immunity.

[56]  J. Russell.  Internal Disintegration Model of Cytotoxic Lymphocyte‐Induced Target Damage , 1983, Immunological reviews.

[57]  H. Young,et al.  IL-7 regulation of cytotoxic lymphocytes: pore-forming protein gene expression, interferon-gamma production, and cytotoxicity of human peripheral blood lymphocytes subsets. , 1991, Cellular immunology.

[58]  P. Lichter,et al.  Human perforin (PRF1) maps to 10q22, a region that is syntenic with mouse chromosome 10. , 1992, Genomics.

[59]  R. Aebersold,et al.  A natural killer cell granule protein that induces DNA fragmentation and apoptosis , 1992, The Journal of experimental medicine.

[60]  L. Young,et al.  Perforin-mediated myocardial damage in acute myocarditis , 1990, The Lancet.

[61]  J. D. Young,et al.  The ninth component of complement and the pore-forming protein (perforin 1) from cytotoxic T cells: structural, immunological, and functional similarities. , 1986, Science.

[62]  D. Hudig,et al.  Proteases and lymphocyte cytotoxic killing mechanisms. , 1993, Current opinion in immunology.

[63]  J. Shiver,et al.  A noncytotoxic mast cell tumor line exhibits potent IgE-dependent cytotoxicity after transfection with the cytolysin/perforin gene , 1991, Cell.

[64]  F. Di Virgilio,et al.  Extracellular ATP as a possible mediator of cell-mediated cytotoxicity. , 1990, Immunology today.

[65]  B. Kwon,et al.  The structure of the mouse lymphocyte pore-forming protein perforin. , 1989, Biochemical and biophysical research communications.

[66]  E. Podack,et al.  Perforin mRNA in primary peritoneal exudate cytotoxic T lymphocytes. , 1989, Journal of immunology.

[67]  Craig W. Reynolds,et al.  Molecular cloning of rat cytolysin. , 1989, Journal of immunology.

[68]  J. D. Young,et al.  Expression of perforin and serine esterases by human gamma/delta T cells , 1991, The Journal of experimental medicine.

[69]  Chau‐Ching Liu,et al.  Identification, isolation, and characterization of a novel cytotoxin in murine cytolytic lymphocytes , 1987, Cell.

[70]  H. Ostergaard,et al.  Cytotoxic T lymphocyte mediated lysis without release of serine esterase , 1987, Nature.

[71]  H. Müller-Eberhard,et al.  The membrane attack complex of complement. , 1986, Annual review of immunology.

[72]  J. Tschopp,et al.  Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways , 1994, Nature.

[73]  B. Kwon,et al.  Identification of a killer cell-specific regulatory element of the mouse perforin gene: an Ets-binding site-homologous motif that interacts with Ets-related proteins , 1993, Molecular and cellular biology.