Identification and characterization of a pore-forming protein of human peripheral blood natural killer cells.

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Structural, functional and immunological similarities between the ninth component of complement (C9) and the lymphocyte pore-forming protein (PFP, perforin) have recently been described (8-10). PFP is shown here to be immunologically related to all other components of the membrane attack complex (MAC) of human complement, namely, C5b-6, C7, C8, and C9. Polyclonal antibodies raised against purified human C5b-6, C7, C8, or C9 react with other components of the MAC and with mouse lymphocyte PFP. The antigenic epitopes shared by human complement proteins and mouse lymphocyte PFP are limited to cysteine-rich domains. Only complement proteins that have been reduced and alkylated elicit the production of crossreactive antibodies when used as immunogens. The nonreduced forms of complement components or lymphocyte PFP neither react with these antibodies nor give rise to crossreactive antibodies. The homologous domains of complement proteins and lymphocyte PFP may play related functions in their attachment to lipid membranes and assembly of membrane lesions.

Section: Discussionmentioning

confidence: 99%

“…Structural, functional and immunological similarities between the ninth component of complement (C9) and the lymphocyte pore-forming protein (PFP, perforin) have recently been described (8)(9)(10) . PFP is shown here to be immunologically related to all other components of the membrane attack complex …”

Section: Discussionmentioning

confidence: 99%

The pore-forming protein (perforin) of cytolytic T lymphocytes is immunologically related to the components of membrane attack complex of complement through cysteine-rich domains.

Young¹,

Liu²,

Leong³

et al. 1986

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mentioning

confidence: 99%

“…PFP is postulated to intercalate the target cell membrane and compromise its osmotic stability; however, the function of SEs in the cytotoxic process is less clear. Intriguing parallels have been drawn between this mechanism and the complement cascade, including the close similarities between the immunological and physicochemical properties ofPFP and C9, the ninth component ofcomplement (7,(10)(11)(12) .Many ofthe granule polypeptides have been purified to homogeneity, and cDNA clones encoding PFP (13-16) and several of the SEs (17-25) have recently been characterized. To further analyze the role of PFP in the cytolytic process and the basis for its immunological and evolutionary relationship to C9, we have investigated the This work was supported in part by U. S.…”

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confidence: 99%

Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10. Similarities to and differences from C9.

Trapani

Kwon

Kozak

et al. 1990

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The molecular mechanisms involved in the delivery of cellular injury or death by CTL and NK cells have not been elucidated (1, 2). The granule-exocytosis model of cellular cytotoxicity, the most closely investigated mechanism to date, postulates that an obligate facet of the delivery of the "lethal hit" is the directional release of cytotoxic polypeptides and other molecules (the granule contents) towards the target cell (3-5). Key molecules in this process are a cytolytic protein termed perforin (5, 6), cytolysin (3), pore-forming protein (PFP)t (4) or C9-related polypeptide (C9RP) (7), and a family of killer cell-specific, highly homologous serine esterases (SE) (8,9). PFP is postulated to intercalate the target cell membrane and compromise its osmotic stability; however, the function of SEs in the cytotoxic process is less clear. Intriguing parallels have been drawn between this mechanism and the complement cascade, including the close similarities between the immunological and physicochemical properties ofPFP and C9, the ninth component ofcomplement (7,(10)(11)(12) .Many ofthe granule polypeptides have been purified to homogeneity, and cDNA clones encoding PFP (13-16) and several of the SEs (17-25) have recently been characterized. To further analyze the role of PFP in the cytolytic process and the basis for its immunological and evolutionary relationship to C9, we have investigated the This work was supported in part by U. S.

“…They showed that, instead of oxygen metabolites, killer cells released a pore-forming protein by granulemediated exocytosis. Young isolated from killer cell granules this "perforin" (260,285,291), as well as two serine esterases (294). Young characterized the lesions that were created by perforin deposition in targets as large ion-carrying pores and visualized the pores by electron microscopy (292).…”

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confidence: 99%

Zanvil Alexander Cohn 1926-1993.

Steinman¹,

Moberg²

1994

SummaryZanvil Alexander Cohn, an editor of this Journal since 1973, died suddenly on June 28, 1993. Cohn is best known as the father of the current era of macrophage biology. Many of his scientific accomplishments are recounted here, beginning with seminal studies on the granules of phagocytes that were performed with his close colleague and former editor of thisJournaI, James Hirsch. Cohn and Hirsch identified the granules as lysosomes that discharged their contents of digestive enzymes into vacuoles containing phagocytosed microbes. These findings were part of the formative era of cell biology and initiated the modern study of endocytosis and cell-mediated resistance to infection. Cohn further explored the endocytic apparatus in pioneering studies of the mouse peritoneal macrophage in culture. He described vesicular inputs from the cell surface and Golgi apparatus and documented the thoroughness of substrate digestion within lysosomal vacuoles that would only permit the egress of monosaccharides and amino acids. These discoveries created a vigorous environment for graduate students, postdoctoral fellows, and junior and visiting faculty. Some of the major findings that emerged from Cohn's collaborations included the radioiodination of the plasma membrane for studies of composition and turnover; membrane recycling during endocytosis; the origin of the mononuclear phagocyte system in situ; the discovery of the dendritic cell system of antigen-presenting cells; the macrophage as a secretory cell, including the release of proteases and large amounts of prostaglandins and leukotrienes; several defined parameters of macrophage activation, especially the ability of T cell-derived lymphokines to enhance killing of tumor cells and intracellular protozoa; the granule discharge mechanism whereby cytotoxic lymphocytes release the pore-forming protein perforin; the signaling of macrophages via myristoylated substrates of protein kinase C; and a tissue culture model in which monocytes emigrate across tight endothelial junctions. In 1983, Cohn turned to a long-standing goal of exploring host resistance directly in humans. He studied leprosy, focusing on the disease site, the parasitized macrophages of the skin. He injected recombinant lymphokines into the skin and found that these molecules elicited several cell-mediated responses. Seeing this potential to enhance host defense in patients, Cohn was extending his clinical studies to AIDS and tuberculosis. Zanvil Cohn was a consummate physician-scientist who nurtured the relationship between cell biology and infectious disease. He guided with a warm but incisive manner the careers of many individuals. He was deeply committed to several institutions of biomedical research; to medicine in the developing world; to The Rockefeller University, especially its programs for graduate study and patient-oriented research;and to the energy and spirit of this Journal.