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Journal articles on the topic 'Perforin'

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Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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1

Urrea Moreno, Ramon, Juana Gil, Carmen Rodriguez-Sainz, Elena Cela, Victor LaFay, Brian Oloizia, Andrew B. Herr, Janos Sumegi, Michael B. Jordan, and Kimberly A. Risma. "Functional assessment of perforin C2 domain mutations illustrates the critical role for calcium-dependent lipid binding in perforin cytotoxic function." Blood 113, no. 2 (January 8, 2009): 338–46. http://dx.doi.org/10.1182/blood-2008-08-172924.

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Abstract Perforin-mediated lymphocyte cytotoxicity is critical for pathogen elimination and immune homeostasis. Perforin disruption of target cell membranes is hypothesized to require binding of a calcium-dependent, lipid-inserting, C2 domain. In a family affected by hemophagocytic lymphohistiocytosis, a severe inflammatory disorder caused by perforin deficiency, we identified 2 amino acid substitutions in the perforin C2 domain: T435M, a previously identified mutant with disputed pathogenicity, and Y438C, a novel substitution. Using biophysical modeling, we predicted that the T435M substitution, but not Y438C, would interfere with calcium binding and thus cytotoxic function. The capacity for cytotoxic function was tested after expression of the variant perforins in rat basophilic leukemia cells and murine cytotoxic T lymphocytes. As predicted, cells transduced with perforin-T435M lacked cytotoxicity, but those expressing perforin-Y438C displayed intact cytotoxic function. Using novel antibody-capture and liposome-binding assays, we found that both mutant perforins were secreted; however, only nonmutated and Y438C-substituted perforins were capable of calcium-dependent lipid binding. In addition, we found that perforin-Y438C was capable of mediating cytotoxicity without apparent proteolytic maturation. This study clearly demonstrates the pathogenicity of the T435M mutation and illustrates, for the first time, the critical role of the human perforin C2 domain for calcium-dependent, cytotoxic function.

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2

Bird, Lucy. "Perforin protection." Nature Reviews Immunology 15, no. 11 (October 16, 2015): 667. http://dx.doi.org/10.1038/nri3926.

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3

Joag, SV. "Perforin in myocarditis." Biomedicine & Pharmacotherapy 45, no. 2-3 (January 1991): 126. http://dx.doi.org/10.1016/0753-3322(91)90138-j.

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4

Ahmed, Najwa, Amal Fayyad, Salimeh Mohammadi, Subhi Hamza, and Abdul Al-Faisal. "Purification of perforin and study expression of perforin in leukemia patient." Egyptian Academic Journal of Biological Sciences. C, Physiology and Molecular Biology 5, no. 2 (December 1, 2013): 1–9. http://dx.doi.org/10.21608/eajbsc.2013.16090.

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5

Kafsack, Björn F. C., and Vern B. Carruthers. "Apicomplexan perforin-like proteins." Communicative & Integrative Biology 3, no. 1 (January 2010): 18–23. http://dx.doi.org/10.4161/cib.3.1.9794.

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6

Arnaout, Ramy A. "Perforin deficiency: fighting unarmed?" Immunology Today 21, no. 11 (November 2000): 592. http://dx.doi.org/10.1016/s0167-5699(00)01730-8.

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7

McDiarmid, S. V., D. G. Farmer, J. S. Kuniyoshi, M. Robert, A. Khadavi, A. Shaked, and R. W. Busuttil. "PERFORIN AND GRANZYME B." Transplantation 59, no. 5 (March 1995): 762–66. http://dx.doi.org/10.1097/00007890-199503150-00021.

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8

Krähenbühl, Olivier, and Jürg Tschopp. "Perforin-induced pore formation." Immunology Today 12, no. 11 (November 1991): 399–402. http://dx.doi.org/10.1016/0167-5699(91)90139-k.

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9

Liu, Chau-Ching, Craig M. Walsh, and John Ding-E. Young. "Perforin: structure and function." Immunology Today 16, no. 4 (April 1995): 194–201. http://dx.doi.org/10.1016/0167-5699(95)80121-9.

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10

Covas, Dimas Tadeu. "Perforin and hematological cancer." Revista Brasileira de Hematologia e Hemoterapia 33, no. 4 (2011): 254–55. http://dx.doi.org/10.5581/1516-8484.20110070.

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11

Švegar, Davorka. "The Role of Perforin." Croatian nursing journal 5, no. 1 (August 23, 2021): 75–82. http://dx.doi.org/10.24141/2/5/1/7.

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Some literature reviews have been carried out about the role of perforin in medicine. The first step involved a systematic search to identify relevant studies published between 2001 and 2019 in the following electronic databases - EBSCO host, Scopus, Science Direct, Web of Science, and Elsevier. By analyzing the available literature, it can be concluded that perforin plays an important role in cytoxical activity of natural killer cells (NK) and CD8+ T cell. NK and CD8+use the same mechanism for destroying target cells. This article cites the disease hemophagocytic lymphohistiocytosis (HLH) which is characterized by heavy abnormalities in the immune system. The point is that this disease is caused by perforin gene mutation. The key is the application of properly sensitized dendritic cells (DCs) because they are effective in immunotherapy against cancer. It may be effective in γ-irradiated colon cancer cell lines HT-29. Growth hormone inhibiting hormone (GIH) induces maturation and activation of DCs. In that way, GIH-Dcs shows increased cytotoxic activity and higher perforin and granzyme expression. So, this means that theoretical research has shown that efficient activity against cancer is induced when DCs are sensitized with γ-irradiated cancer cells. In that way, through a direct increase of cytotoxicity and indirect T cell activation,there can beanti-tumor activity. It is suggested to continue scientific research about the role of perforin in the future.

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12

Browne, Kylie A., Elizabeth Blink, Vivien R. Sutton, Christopher J. Froelich, David A. Jans, and Joseph A. Trapani. "Cytosolic Delivery of Granzyme B by Bacterial Toxins: Evidence that Endosomal Disruption, in Addition to Transmembrane Pore Formation, Is an Important Function of Perforin." Molecular and Cellular Biology 19, no. 12 (December 1, 1999): 8604–15. http://dx.doi.org/10.1128/mcb.19.12.8604.

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ABSTRACT Granule-mediated cell killing by cytotoxic lymphocytes requires the combined actions of a membranolytic protein, perforin, and granule-associated granzymes, but the mechanism by which they jointly kill cells is poorly understood. We have tested a series of membrane-disruptive agents including bacterial pore-forming toxins and hemolytic complement for their ability to replace perforin in facilitating granzyme B-mediated cell death. As with perforin, low concentrations of streptolysin O and pneumolysin (causing <10%51Cr release) permitted granzyme B-dependent apoptosis of Jurkat and Yac-1 cells, but staphylococcal alpha-toxin and complement were ineffective, regardless of concentration. The ensuing nuclear apoptotic damage was caspase dependent and included cleavage of poly(ADP-ribose) polymerase, suggesting a mode of action similar to that of perforin. The plasma membrane lesions formed at low dose by perforin, pneumolysin, and streptolysin did not permit diffusion of fluorescein-labeled proteins as small as 8 kDa into the cell, indicating that large membrane defects are not necessary for granzymes (32 to 65 kDa) to enter the cytosol and induce apoptosis. The endosomolytic toxin, listeriolysin O, also effected granzyme B-mediated cell death at concentrations which produced no appreciable cell membrane damage. Cells pretreated with inhibitors of endosomal trafficking such as brefeldin A took up granzyme B normally but demonstrated seriously impaired nuclear targeting of granzyme B when perforin was also added, indicating that an important role of perforin is to disrupt vesicular protein trafficking. Surprisingly, cells exposed to granzyme B with perforin concentrations that produced nearly maximal 51Cr release (1,600 U/ml) also underwent apoptosis despite excluding a 8-kDa fluorescein-labeled protein marker. Only at concentrations of >4,000 U/ml were perforin pores demonstrably large enough to account for transmembrane diffusion of granzyme B. We conclude that pore formation may allow granzyme B direct cytosolic access only when perforin is delivered at very high concentrations, while perforin’s ability to disrupt endosomal trafficking may be crucial when it is present at lower concentrations or in killing cells that efficiently repair perforin pores.

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13

Andersson, J. P. "Perforin deficiency in HIV pathogenesis." International Journal of Infectious Diseases 6 (June 2002): S9. http://dx.doi.org/10.1016/s1201-9712(02)90195-5.

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14

Clark, William R. "The hole truth about perforin." Nature 369, no. 6475 (May 1994): 16–17. http://dx.doi.org/10.1038/369016a0.

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15

LIU, CHAU-CHING, PEDRO M. PERSECHINIL, and JOHN DING-E. YOUNG. "Perforin and Lymphocyte-mediated Cytolysis." Immunological Reviews 146, no. 1 (August 1995): 145–75. http://dx.doi.org/10.1111/j.1600-065x.1995.tb00688.x.

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16

Katano, Harutaka, and Jeffrey I. Cohen. "Perforin and lymphohistiocytic proliferative disorders." British Journal of Haematology 128, no. 6 (March 2005): 739–50. http://dx.doi.org/10.1111/j.1365-2141.2004.05305.x.

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17

Tadokoro, Hiroko, Akiyoshi Hirayama, Ryuhei Kudo, Masako Hasebe, Yusuke Yoshioka, Juntaro Matsuzaki, Yusuke Yamamoto, Masahiro Sugimoto, Tomoyoshi Soga, and Takahiro Ochiya. "Adenosine leakage from perforin-burst extracellular vesicles inhibits perforin secretion by cytotoxic T-lymphocytes." PLOS ONE 15, no. 4 (April 10, 2020): e0231430. http://dx.doi.org/10.1371/journal.pone.0231430.

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18

Nickell, Steven P., and Divya Sharma. "Trypanosoma cruzi: Roles for Perforin-Dependent and Perforin-Independent Immune Mechanisms in Acute Resistance." Experimental Parasitology 94, no. 4 (April 2000): 207–16. http://dx.doi.org/10.1006/expr.2000.4498.

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19

Muralitharan, Shanmugakonar, Zakia Al Lamki, David Dennison, Brian Sidney Christie, Yasser A. Wali, Mathew Zachariah, Marc Romana, Riad Bayoumi, and Rajagopal Krishnamoorthy. "An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression." American Journal of Hematology 78, no. 1 (2004): 59–63. http://dx.doi.org/10.1002/ajh.20256.

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20

Jones, J., and B. P. Morgan. "Killing of cells by perforin. Resistance to killing is not due to diminished binding of perforin to the cell membrane." Biochemical Journal 280, no. 1 (November 15, 1991): 199–204. http://dx.doi.org/10.1042/bj2800199.

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Different cell types vary widely in their susceptibility to killing by the pore-forming cytolytic molecule perforin. In particular, the cells responsible for synthesis of perforin, i.e. cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, are very resistant to cytolysis by this molecule. It has previously been suggested that resistance is due, at least in part, to diminished binding of perforin to these cells. The purpose of the present study was to compare binding of perforin to sensitive and resistant cell types. To this end, perforin was biosynthetically labelled prior to purification. The purified labelled protein was then utilized to obtain a direct measure of the amount of perforin bound to cells during attack. Resistant cells (CTL, neutrophils) bound at least as much perforin as did sensitive cells (K562, HL60 etc.), indicating that resistance to perforin involves mechanisms operating after binding of the lytic molecule.

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21

Oshimi, K., Y. Shinkai, K. Okumura, Y. Oshimi, and H. Mizoguchi. "Perforin gene expression in granular lymphocyte proliferative disorders." Blood 75, no. 3 (February 1, 1990): 704–8. http://dx.doi.org/10.1182/blood.v75.3.704.704.

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Abstract By Northern blot analysis using a cDNA clone of the perforin gene, we studied the levels of perforin mRNA in peripheral blood mononuclear cells from 11 cases of granular lymphocyte-proliferative disorders (GLPDs). The granular lymphocytes studied were characterized by morphologic, immunophenotypic, and immunogenotypic analyses. Cytolytic functions of the lymphocytes assayed included nonmajor histocompatibility complex-requiring cytotoxicity, anti-CD3-redirected cytotoxicity, antibody-dependent cellular cytotoxicity, and lectin- dependent cellular cytotoxicity. The results showed that in lymphocytes with strong cytolytic functions high levels of perforin mRNA existed, whereas in lymphocytes with weak or undetectable levels of cytolytic functions, low levels of perforin mRNA existed. Because the levels of perforin mRNA correlated with those of cytolytic functions, perforin is probably a mediator in cytolytic functions of granular lymphocytes in patients with GLPDs. When the lymphocytes were cultured for 1 day, however, the levels of cytolytic activity were increased, and those of perforin mRNA were decreased. Therefore, we cannot rule out the possibility that factors other than perforin protein are involved in the cytolytic functions of granular lymphocytes.

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22

Oshimi, K., Y. Shinkai, K. Okumura, Y. Oshimi, and H. Mizoguchi. "Perforin gene expression in granular lymphocyte proliferative disorders." Blood 75, no. 3 (February 1, 1990): 704–8. http://dx.doi.org/10.1182/blood.v75.3.704.bloodjournal753704.

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By Northern blot analysis using a cDNA clone of the perforin gene, we studied the levels of perforin mRNA in peripheral blood mononuclear cells from 11 cases of granular lymphocyte-proliferative disorders (GLPDs). The granular lymphocytes studied were characterized by morphologic, immunophenotypic, and immunogenotypic analyses. Cytolytic functions of the lymphocytes assayed included nonmajor histocompatibility complex-requiring cytotoxicity, anti-CD3-redirected cytotoxicity, antibody-dependent cellular cytotoxicity, and lectin- dependent cellular cytotoxicity. The results showed that in lymphocytes with strong cytolytic functions high levels of perforin mRNA existed, whereas in lymphocytes with weak or undetectable levels of cytolytic functions, low levels of perforin mRNA existed. Because the levels of perforin mRNA correlated with those of cytolytic functions, perforin is probably a mediator in cytolytic functions of granular lymphocytes in patients with GLPDs. When the lymphocytes were cultured for 1 day, however, the levels of cytolytic activity were increased, and those of perforin mRNA were decreased. Therefore, we cannot rule out the possibility that factors other than perforin protein are involved in the cytolytic functions of granular lymphocytes.

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23

Fraser, Stephanie A., Marek Michalak, William H. Welch, and Dorothy Hudig. "Calreticulin, a component of the endoplasmic reticulum and of cytotoxic lymphocyte granules, regulates perforin-mediated lysis in the hemolytic model system." Biochemistry and Cell Biology 76, no. 5 (October 1, 1998): 881–87. http://dx.doi.org/10.1139/o98-080.

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Cytotoxic lymphocytes kill virally infected cells with specialized cytotoxic granules containing perforin, a protein that forms toxic pores in the target cell membrane. These specialized cytotoxic granules also contain calreticulin, an endoplasmic reticulum chaperone protein. The calcium-independent association of perforin and calreticulin prompted our evaluation of calreticulin's potential to function as a regulatory molecule that protects cytotoxic lymphocytes from their own perforin. We report here that 10-7 M calreticulin blocked perforin-mediated lysis in the hemolytic model system using erythrocytes as targets. Previously, we found that millimolar levels of calcium in the hemolytic assays dissociate high-affinity perforin-calreticulin complexes, which makes it unlikely that perforin associates with calreticulin in solution when hemolysis is blocked. Calreticulin may affect perforin at the erythrocyte membrane. We observed calcium-dependent binding of calreticulin to erythrocyte membranes with a Kd of 2.7 × 10-7 M and a saturation average of 105 molecules calreticulin per erythrocyte. At concentrations that blocked hemolysis, calreticulin occupied many of the calreticulin membrane-binding sites and was in molar excess of perforin. These observations open the possibilities that membrane-bound calreticulin prevents hydrophobic entry of perforin into membranes and (or) prevents perforin from assembling into polyperforin pores.Key words: calreticulin, cytotoxicity, perforin.

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24

Winkler, U., S. A. Fraser, and D. Hudig. "Perforin-Enhancing Protein, a Low Molecular Weight Protein of Cytotoxic Lymphocyte Granules, Enhances Perforin Lysis." Biochemical and Biophysical Research Communications 236, no. 1 (July 1997): 34–39. http://dx.doi.org/10.1006/bbrc.1997.6899.

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25

Varela, Mónica, Gabriel Forn-Cuní, Sonia Dios, Antonio Figueras, and Beatriz Novoa. "Proinflammatory Caspase A Activation and an Antiviral State Are Induced by a Zebrafish Perforin after Possible Cellular and Functional Diversification from a Myeloid Ancestor." Journal of Innate Immunity 8, no. 1 (June 18, 2015): 43–56. http://dx.doi.org/10.1159/000431287.

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In mammals, perforins play a central role in the granule-dependent cell death induced by natural killer T cells and cytotoxic T lymphocytes, and participate both in the defense against virus-infected and neoplastic cells and in the recognition of nonself molecules by the immune system. Little is known about fish perforin genes. We examined the zebrafish with the aim of increasing our knowledge about the role of perforins. We characterized 6 perforin genes in the zebrafish genome, and we studied them at the evolutionary level in combination with expression patterns in several tissues and cell populations, during both larval development and in the course of a viral infection. Our results suggest the specialization of different cell types in the production of perforins. Moreover, functional diversification during the evolution of these molecules could be inferred from this study. In particular, one of the genes, prf19b, which is mainly produced by myeloid cells, seemed to be involved in antiviral defense, conferring protection after an in vivo infection.

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26

Cellerai, Cristina, Matthieu Perreau, Virginie Rozot, Felicitas Bellutti Enders, Giuseppe Pantaleo, and Alexandre Harari. "Proliferation Capacity and Cytotoxic Activity Are Mediated by Functionally and Phenotypically Distinct Virus-Specific CD8 T Cells Defined by Interleukin-7Rα (CD127) and Perforin Expression." Journal of Virology 84, no. 8 (February 3, 2010): 3868–78. http://dx.doi.org/10.1128/jvi.02565-09.

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ABSTRACT Cytotoxicity and proliferation capacity are key functions of antiviral CD8 T cells. In the present study, we investigated a series of markers to define these functions in virus-specific CD8 T cells. We provide evidence that there is a lack of coexpression of perforin and CD127 in human CD8 T cells. CD127 expression on virus-specific CD8 T cells correlated positively with proliferation capacity and negatively with perforin expression and cytotoxicity. Influenza virus-, cytomegalovirus-, and Epstein-Barr virus/human immunodeficiency virus type 1-specific CD8 T cells were predominantly composed of CD127+ perforin−/CD127− perforin+, and CD127−/perforin− CD8 T cells, respectively. CD127−/perforin− and CD127−/perforin+ cells expressed significantly more PD-1 and CD57, respectively. Consistently, intracellular cytokine (gamma interferon, tumor necrosis factor alpha, and interleukin-2 [IL-2]) responses combined to perforin detection confirmed that virus-specific CD8 T cells were mostly composed of either perforin+/IL-2− or perforin−/IL-2+ cells. In addition, perforin expression and IL-2 secretion were negatively correlated in virus-specific CD8 T cells (P < 0.01). As previously shown for perforin, changes in antigen exposure modulated also CD127 expression. Based on the above results, proliferating (CD127+/IL-2-secreting) and cytotoxic (perforin+) CD8 T cells were contained within phenotypically distinct T-cell populations at different stages of activation or differentiation and showed different levels of exhaustion and senescence. Furthermore, the composition of proliferating and cytotoxic CD8 T cells for a given antiviral CD8 T-cell population appeared to be influenced by antigen exposure. These results advance our understanding of the relationship between cytotoxicity, proliferation capacity, the levels of senescence and exhaustion, and antigen exposure of antiviral memory CD8 T cells.

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27

Zheng, L. M., C. C. Liu, D. M. Ojcius, and J. D. Young. "Expression of lymphocyte perforin in the mouse uterus during pregnancy." Journal of Cell Science 99, no. 2 (June 1, 1991): 317–23. http://dx.doi.org/10.1242/jcs.99.2.317.

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In situ hybridization and immunofluorescence were used to study the expression of a lymphocyte pore-forming protein (perforin) in the uterus of pregnant mice. Cells expressing perforin mRNA were detected as early as gestation day 5, whereas perforin protein was detected one or two days later. Although the number of cells expressing both perforin mRNA and perforin protein varied subsequently with time, they were consistently observed from the day of implantation until parturition. The highest levels of mRNA expression were observed sometime during midgestation. The high abundance of this cytolytic protein in the metrial gland during pregnancy and the time course of its expression thus suggest that GMG perforin expression is tightly regulated, probably hormonally, by the uterus, and that GMG cell perforin plays an important role in the normal completion of pregnancy.

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28

Hausmann, Jürgen, Karin Schamel, and Peter Staeheli. "CD8+ T Lymphocytes Mediate Borna Disease Virus-Induced Immunopathology Independently of Perforin." Journal of Virology 75, no. 21 (November 1, 2001): 10460–66. http://dx.doi.org/10.1128/jvi.75.21.10460-10466.2001.

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ABSTRACT Perforin-mediated lysis of target cells is the major antiviral effector mechanism of CD8+ T lymphocytes. We have analyzed the role of perforin in a mouse model for CD8+T-cell-mediated central nervous system (CNS) immunopathology induced by Borna disease virus. When a defective perforin gene was introduced into the genetic background of the Borna disease-susceptible mouse strain MRL, the resulting perforin-deficient mice developed strong neurological disease in response to infection indistinguishable from that of their perforin-expressing littermates. The onset of disease was slightly delayed. Brains of diseased perforin-deficient mice showed similar amounts and a similar distribution of CD8+ T cells as wild-type animals. Perforin deficiency had no impact on the kinetics of viral spread through the CNS. Unlike brain lymphocytes from diseased wild-type mice, lymphocytes from perforin-deficient MRL mice showed no in vitro cytolytic activity towards target cells expressing the nucleoprotein of Borna disease virus. Taken together, these results demonstrate that CD8+ T cells mediate Borna disease independent of perforin. They further suggest that the pathogenic potential of CNS-infiltrating CD8+ T cells does not primarily reside in their lytic activity but rather in other functions.

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29

Kogawa, Kazuhiro, Susan M. Lee, Joyce Villanueva, Daniel Marmer, Janos Sumegi, and Alexandra H. Filipovich. "Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members." Blood 99, no. 1 (January 1, 2002): 61–66. http://dx.doi.org/10.1182/blood.v99.1.61.

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Mutations in the perforin gene have been described in some patients with hemophagocytic lymphohistiocytosis (HLH), but the role of perforin defects in the pathogenesis of HLH remains unclear. Four-color flow cytometric analysis was used to establish normal patterns of perforin expression for control subjects of all ages, and patterns of perforin staining in cytotoxic lymphocytes (natural killer [NK] cells, CD8+ T cells, CD56+ T cells) from patients with HLH and their family members were studied. Eleven unrelated HLH patients and 19 family members were analyzed prospectively. Four of the 7 patients with primary HLH showed lack of intracellular perforin in all cytotoxic cell types. All 4 patients showed mutations in the perforin gene. Their parents, obligate carriers of perforin mutations, had abnormal perforin-staining patterns. Analysis of cytotoxic cells from the other 3 patients with primary HLH and remaining family members had normal percentages of perforin-positive cytotoxic cells. On the other hand, the 4 patients with Epstein-Barr virus–associated HLH typically had depressed numbers of NK cells but markedly increased proportions of CD8+ T cells with perforin expression. Four-color flow cytometry provides diagnostic information that, in conjunction with evidence of reduced NK function, may speed the identification of life-threatening HLH in some families and direct further genetic studies of the syndrome.

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30

Nakamura, Tsukasa, Isao Ebihara, Shiori Osada, Ko Okumura, Yasuhiko Tomino, and Hikaru Koide. "Perforin gene expression in T lymphocytes correlates with disease activity in immunoglobulin A nephropathy." Clinical Science 82, no. 4 (April 1, 1992): 461–68. http://dx.doi.org/10.1042/cs0820461.

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1. We studied perforin gene expression in T lymphocytes obtained from 26 patients with IgA nephropathy and from 15 healthy age-matched control subjects. 2. The majority of patients with IgA nephropathy (96%) had elevated perforin mRNA expression, whereas no perforin mRNA expression was detected in the T lymphocytes of normal control subjects. 3. A positive correlation was noted between perforin mRNA expression and urinary protein excretion. 4. Perforin mRNA expression correlated also with the histopathology in the renal tissue of patients with IgA nephropathy. 5. Sixty per cent of patients with grade III or IV histopathology had high perforin mRNA expression in T lymphocytes [more than (++)]. 6. These studies suggest that disregulation of perforin gene expression in T lymphocytes may be associated with the progression of IgA nephropathy and could be used as an indicator of disease activity.

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31

Voskoboinik, Ilia, Marie-Claude Thia, Annette De Bono, Kylie Browne, Erika Cretney, Jacob T. Jackson, Phillip K. Darcy, Stephen M. Jane, Mark J. Smyth, and Joseph A. Trapani. "The Functional Basis for Hemophagocytic Lymphohistiocytosis in a Patient with Co-inherited Missense Mutations in the Perforin (PFN1) Gene." Journal of Experimental Medicine 200, no. 6 (September 13, 2004): 811–16. http://dx.doi.org/10.1084/jem.20040776.

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About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated (∼45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure–function relationships for lymphocyte perforin.

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32

Thiery, Jerome, Dennis Keefe, Saviz Saffarian, Denis Martinvalet, Michael Walch, Emmanuel Boucrot, Tomas Kirchhausen, and Judy Lieberman. "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, no. 8 (February 25, 2010): 1582–93. http://dx.doi.org/10.1182/blood-2009-10-246116.

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Abstract Cytotoxic T lymphocytes and natural killer cells destroy target cells via the polarized exocytosis of lytic effector proteins, perforin and granzymes, into the immunologic synapse. How these molecules enter target cells is not fully understood. It is debated whether granzymes enter via perforin pores formed at the plasma membrane or whether perforin and granzymes are first endocytosed and granzymes are then released from endosomes into the cytoplasm. We previously showed that perforin disruption of the plasma membrane induces a transient Ca2+ flux into the target cell that triggers a wounded membrane repair response in which lysosomes and endosomes donate their membranes to reseal the damaged membrane. Here we show that perforin activates clathrin- and dynamin-dependent endocytosis, which removes perforin and granzymes from the plasma membrane to early endosomes, preserving outer membrane integrity. Inhibiting clathrin- or dynamin-dependent endocytosis shifts death by perforin and granzyme B from apoptosis to necrosis. Thus by activating endocytosis to preserve membrane integrity, perforin facilitates granzyme uptake and avoids the proinflammatory necrotic death of a membrane-damaged cell.

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33

Kanvinde, Purva, Prasad Taur, Ankit Parmar, Mohammad Naseer, Shraddha Chandak, Sangeeta Mudaliar, Archana Swami, et al. "Perforin deficiency: A tertiary centre experience." Pediatric Hematology Oncology Journal 2, no. 2 (2017): S3. http://dx.doi.org/10.1016/j.phoj.2017.11.133.

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34

Voskoboinik, Ilia, and Joseph A. Trapani. "Addressing the mysteries of perforin function." Immunology & Cell Biology 84, no. 1 (February 2006): 66–71. http://dx.doi.org/10.1111/j.1440-1711.2005.01409.x.

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35

Zheng, Li Mou, David M. Ojcius, and John Ding-E. Young. "Perforin-Expressing Cells during Spontaneous Abortion1." Biology of Reproduction 48, no. 5 (May 1, 1993): 1014–19. http://dx.doi.org/10.1095/biolreprod48.5.1014.

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36

Moreno-Hagelsieb, Gabriel, Bennett Vitug, Arturo Medrano-Soto, and Milton H. Saier Jr. "The Membrane Attack Complex/Perforin Superfamily." Journal of Molecular Microbiology and Biotechnology 27, no. 4 (2017): 252–67. http://dx.doi.org/10.1159/000481286.

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The membrane attack complex/perforin (MACPF) superfamily consists of a diverse group of proteins involved in bacterial pathogenesis and sporulation as well as eukaryotic immunity, embryonic development, neural migration and fruiting body formation. The present work shows that the evolutionary relationships between the members of the superfamily, previously suggested by comparison of their tertiary structures, can also be supported by analyses of their primary structures. The superfamily includes the MACPF family (TC 1.C.39), the cholesterol-dependent cytolysin (CDC) family (TC 1.C.12.1 and 1.C.12.2) and the pleurotolysin pore-forming (pleurotolysin B) family (TC 1.C.97.1), as revealed by expansion of each family by comparison against a large protein database, and by the comparisons of their hidden Markov models. Clustering analyses demonstrated grouping of the CDC homologues separately from the 12 MACPF subfamilies, which also grouped separately from the pleurotolysin B family. Members of the MACPF superfamily revealed a remarkably diverse range of proteins spanning eukaryotic, bacterial, and archaeal taxonomic domains, with notable variations in protein domain architectures. Our strategy should also be helpful in putting together other highly divergent protein families.

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37

Ahmed, Khaja R., Taylor B. Guo, and Karl K. Gaal. "ISLET REJECTION IN PERFORIN-DEFICIENT MICE." Transplantation 63, no. 7 (April 1997): 951–57. http://dx.doi.org/10.1097/00007890-199704150-00008.

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38

Zipursky, Alvin. "Perforin Deficiency and Familial Hemophagocytic Lymphohistiocytosis." Pediatric Research 49, no. 1 (January 2001): 3. http://dx.doi.org/10.1203/00006450-200101000-00003.

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39

Brennan, A. J., J. Chia, J. A. Trapani, and I. Voskoboinik. "Perforin deficiency and susceptibility to cancer." Cell Death & Differentiation 17, no. 4 (January 15, 2010): 607–15. http://dx.doi.org/10.1038/cdd.2009.212.

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40

Lichtenheld, Mathias G., Kristin J. Olsen, Ping Lu, David M. Lowrey, Arif Hameed, Hans Hengartner, and Eckhard R. Podack. "Structure and function of human perforin." Nature 335, no. 6189 (September 1988): 448–51. http://dx.doi.org/10.1038/335448a0.

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41

Levitt, D. "Gramicidin, VDAC, porin and perforin channels." Current Opinion in Cell Biology 2, no. 4 (August 1990): 689–94. http://dx.doi.org/10.1016/0955-0674(90)90112-r.

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42

Voskoboinik, Ilia, Vivien R. Sutton, Annette Ciccone, Colin M. House, Jenny Chia, Phillip K. Darcy, Hideo Yagita, and Joseph A. Trapani. "Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function." Blood 110, no. 4 (August 15, 2007): 1184–90. http://dx.doi.org/10.1182/blood-2007-02-072850.

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Abstract Perforin (PRF), a pore-forming protein expressed in cytotoxic lymphocytes, plays a key role in immune surveillance and immune homeostasis. The A91V substitution has a prevalence of 8% to 9% in population studies. While this variant has been suspected of predisposing to various disorders of immune homeostasis, its effect on perforin's function has not been elucidated. Here we complemented, for the first time, the cytotoxic function of perforin-deficient primary cytotoxic T lymphocytes (CTLs) with wild-type (hPRF-WT) and A91V mutant (hPRF-A91V) perforin. The cytotoxicity of hPRF-A91V–expressing cells was about half that of hPRF-WT–expressing counterparts and coincided with a moderate reduction in hPRF-A91V expression. By contrast, the reduction in cytotoxic function was far more pronounced (more than 10-fold) when purified proteins were tested directly on target cells. The A91V substitution can therefore be manifested by abnormalities at both the lymphocyte (presynaptic) and target cell (postsynaptic) levels. However, the severe intrinsic defect in activity can be partly rescued by expression in the physiological setting of an intact CTL. These findings provide the first direct evidence that hPRF-A91V is functionally abnormal and provides a rationale for why it may be responsible for disordered immune homeostasis if inherited with another dysfunctional perforin allele.

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43

Solomou, Elena E., Federica Gibellini, Brian Stewart, Daniela Malide, Maria Berg, Valeria Visconte, Spencer Green, Richard Childs, Stephen J. Chanock, and Neal S. Young. "Perforin gene mutations in patients with acquired aplastic anemia." Blood 109, no. 12 (June 15, 2007): 5234–37. http://dx.doi.org/10.1182/blood-2006-12-063495.

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Abstract Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural killer cells. Inherited perforin mutations account for 20% to 40% of familial hemophagocytic lymphohistiocytosis, a fatal disease of early childhood characterized by the absence of functional perforin. Aplastic anemia, the paradigm of immune-mediated bone marrow failure syndromes, is characterized by hematopoietic stem cell destruction by activated T cells and Th1 cytokines. We examined whether mutations in the perforin gene occurred in acquired aplastic anemia. Three nonsynonymous PRF1 mutations among 5 unrelated patients were observed. Four of 5 patients with the mutations showed some hemophagocytosis in the bone marrow at diagnosis. Perforin protein levels in these patients were very low or absent, and perforin granules were completely absent. Natural killer (NK) cell cytotoxicity from these patients was significantly decreased. Our data suggest that PRF1 genetic alterations help explain the aberrant proliferation and activation of cytotoxic T cells and may represent genetic risk factors for bone marrow failure.

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44

Zheng, L. M., S. V. Joag, M. B. Parr, E. L. Parr, and J. D. Young. "Perforin-expressing granulated metrial gland cells in murine deciduoma." Journal of Experimental Medicine 174, no. 5 (November 1, 1991): 1221–26. http://dx.doi.org/10.1084/jem.174.5.1221.

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It has previously been shown that granulated metrial gland (GMG) cells of the pregnant uterus express abundant quantities of the lymphocyte pore-forming protein, perforin. No perforin was present before implantation of the embryo, but large numbers of perforin-producing GMG cells were observed after implantation, which coincides with decidualization of the uterus. The possible source of the activation factors responsible for perforin gene induction in GMG cells was studied here with the pseudopregnancy model, in which cervical stimulation of mice during estrus leads to a series of hormonal changes resembling those seen in pregnancy, but in the absence of an embryo. Subsequent stimulation of the uterus of pseudopregnant mice with oil causes the stimulated portion of the endometrium to differentiate into decidual tissue. Perforin-containing GMG cells were in fact present in the deciduomata, but not in adjacent nondecidualized tissues of the same mice. These results suggest that maternal factors associated with decidual tissue are responsible for the local expression of perforin in GMG cells.

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Jiang, S. B., P. M. Persechini, A. Zychlinsky, C. C. Liu, B. Perussia, and J. D. Young. "Resistance of cytolytic lymphocytes to perforin-mediated killing. Lack of correlation with complement-associated homologous species restriction." Journal of Experimental Medicine 168, no. 6 (December 1, 1988): 2207–19. http://dx.doi.org/10.1084/jem.168.6.2207.

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CTL and NK cells resist self-mediated killing and lysis by their own pore-forming protein (PFP; perforin). Perforin, like C, lyses RBC. Efficient C-mediated lysis of RBC occurs when both C and RBC are from different species (homologous species restriction). A protective surface protein (C8-binding protein, homologous restriction factor) has been reported to mediate both homologous species restriction in C-dependent cytolysis and protection of some target cells against perforin-induced lysis. We show here that perforin, unlike C, lyses target cells across a variety of species, including the homologous one, while the same target cell populations resist the attack by homologous C. Perforin-containing extracts of CTL and LAK/NK cells from three species (rat, mouse, and human) and purified mouse perforin were tested against RBC from 10 different species, several nucleated target cell lines, and one primary cell population (thymocytes). While resisting lysis by homologous C, most of these cell types were lysed effectively by perforin without any homologous restriction pattern. CTL and NK cells, like other nucleated targets, are resistant to lysis by homologous but not heterologous C; however, these cell types are resistant to both homologous and heterologous perforin. Together, our results suggest that the protective mechanisms associated with C- and perforin-mediated lysis are distinct.

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46

Voskoboinik, Ilia, Marie-Claude Thia, and Joseph A. Trapani. "A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis." Blood 105, no. 12 (June 15, 2005): 4700–4706. http://dx.doi.org/10.1182/blood-2004-12-4935.

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Abstract Up to 60% of cases of the autosomal recessive immunodeficiency hemophagocytic lymphohistiocytosis (HLH) are associated with mutations in the perforin (PRF1) gene. In this study, we expressed wild-type and mutated perforin in rat basophil leukemia cells to study the effect on lytic function of the substitutions A91V and N252S (commonly considered to be neutral polymorphisms) and 22 perforin missense substitutions first identified in HLH patients. Surprisingly, we found that A91V perforin was expressed at reduced levels compared with wild-type perforin, resulting in partial loss of lytic capacity. In contrast, expression and function of N252S-substituted perforin were normal. Most HLH-associated mutations resulted in protein degradation (probably due to misfolding) and complete loss of perforin activity, the exception being R232H, which retained approximately 30% wild-type activity. Several other mutated proteins (H222Q, C73R, F157V, and D313V) had no detectable lytic activity but were expressed at normal levels, suggesting that their functional defect might map downstream at the level of the target cell membrane. One further perforin substitution identified in an HLH patient (V183G) was normally expressed and displayed normal lysis. This report represents the first systematic functional analysis of HLH-associated missense mutations and the 2 most common perforin polymorphisms. (Blood. 2005;105:4700-4706)

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47

Kägi, David, Bernhard Odermatt, Peter Seiler, Rolf M. Zinkernagel, Tak W. Mak, and Hans Hengartner. "Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice." Journal of Experimental Medicine 186, no. 7 (October 6, 1997): 989–97. http://dx.doi.org/10.1084/jem.186.7.989.

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To investigate the role of T cell–mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4+ and CD8+ T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for β cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic β cell loss by less efficient secondary effector mechanisms.

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48

Carmo, Marlene, Kimberly A. Risma, Paritha Arumugam, Swati Tiwari, Adrianne E. Hontz, Claudia A. Montiel-Equihua, Maria E. Alonso-Ferrero, et al. "Perforin Gene Transfer Into Hematopoietic Stem Cells Improves Immune Dysregulation in Murine Models of Perforin Deficiency." Molecular Therapy 23, no. 4 (April 2015): 737–45. http://dx.doi.org/10.1038/mt.2014.242.

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49

Brennan, Amelia J., Ruby H. P. Law, Paul J. Conroy, Tahereh Noori, Natalya Lukoyanova, Helen Saibil, Hideo Yagita, et al. "Perforin proteostasis is regulated through its C2 domain: supra-physiological cell death mediated by T431D-perforin." Cell Death & Differentiation 25, no. 8 (February 7, 2018): 1517–29. http://dx.doi.org/10.1038/s41418-018-0057-z.

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50

Berthou, Christian, Jean-François Bourge, Yuehe Zhang, Annie Soulié, Daniela Geromin, Yves Denizot, François Sigaux, and Marilyne Sasportes. "Interferon-γ–induced membrane PAF-receptor expression confers tumor cell susceptibility to NK perforin-dependent lysis." Blood 95, no. 7 (April 1, 2000): 2329–36. http://dx.doi.org/10.1182/blood.v95.7.2329.

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Abstract Perforin is known to display a membranolytic activity on tumor cells. Nevertheless, perforin release during natural killer (NK)–cell activation is not sufficient to induce membrane target-cell damage. On the basis of the ability of perforin to interact with phospholipids containing a choline phosphate headgroup, we identify the platelet-activating factor (PAF) and its membrane receptor as crucial components in tumor cell killing activity of human resting NK cells. We demonstrate for the first time that upon activation, naive NK cells release the choline phosphate–containing lysolipid PAF, which binds to perforin and acts as an agonist on perforin-induced membrane damage. PAF is known to incorporate cell membranes using a specific receptor. Here we show that interferon-γ (IFN–γ) secreted from activated NK cells ends in PAF-receptor expression on perforin-sensitive K562 cells but not on perforin-resistant Daudi cells. In order to prove the capacity of PAF to interact simultaneously with its membrane PAF receptor and with perforin, we successfully co-purified the 3 components in the presence of bridging PAF molecules. The functional activity of this complex was further examined. The aim was to determine whether membrane PAF-receptor expression on tumor cells, driven to express this receptor, could render them sensitive to the perforin lytic pathway. The results confirmed that transfection of the PAF-receptor complementary DNA into major histocompatibility complex class I and Fas-receptor negative tumor cells restored susceptibility to naive NK cells and perforin attack. Failure of IFN-γ to induce membrane PAF receptor constitutes the first described mechanism for tumor cells to resist the perforin lytic pathway.

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