Cloning, analysis, and expression of murine perforin 1 cDNA, a component of cytolytic T-cell granules with homology to complement component C9.

Lowrey, David M.; Aebischer, Toni; Olsen, Kristin J.; Lichtenheld, Mathias G.; Rupp, Fabio; Hengartner, Hans; Podack, Eckhard R.

doi:10.1073/pnas.86.1.247

Cited by 94 publications

(41 citation statements)

References 38 publications

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“…[14][15][16][17][18][19] Sequence comparison revealed a striking similarity between the two proteins within a short region in their middle part, which was named the 'membrane attack complex/perforin' (MACPF) domain. 16,20,21 Initial characterization of PRF revealed that its pore-forming activity at the phospholipid membrane was calcium dependent.…”

Section: Perforin Biologymentioning

confidence: 99%

Perforin deficiency and susceptibility to cancer

et al. 2010

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Cytotoxic lymphocytes (CLs) are the killer cells that destroy intracellular pathogen-infected and transformed cells, predominantly through the cytotoxic granule-mediated death pathway. Soluble cytotoxic granule components, including pore-forming perforin and pro-apoptotic serine proteases, granzymes, synergize to induce unscheduled apoptosis of the target cell. A complete loss of CL function results in an aggressive immunoregulatory disorder, familial hemophagocytic lymphohistiocytosis, whereas a partial loss of function seems to be a factor strongly predisposing to hematological malignancies. This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology. Cell Death and Differentiation (2010) 17, 607-615; doi:10.1038/cdd.2009; published online 15 January 2010Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, collectively called cytotoxic lymphocytes (CLs), kill virusinfected and transformed cells through a number of contactdependent mechanisms. 1,2 Engagement of death receptors by membrane-bound members of the TNF superfamily of death ligands is critical for maintaining lymphoid homeostasis in the host. By contrast, studies of gene deficiencies indicate that defects of the granule exocytosis pathway result in a failure to eliminate infected cells or those that pose a risk of subsequent malignancy. Although cytotoxic granules contain diverse toxins that together contribute to apoptosis induction, this review will deal exclusively with the critical role of the pore-forming protein perforin (PRF) as an essential enabler of target-cell apoptosis, and its more recently described role as a potential 'extrinsic' tumor suppressor.Perforin is a 67-kDa pore-forming protein that is stored and released from the secretory granules (SGs) of CLs along with a number of pro-apoptotic serine protease granzymes that display broad substrate specificities. 3 Following exocytic release, PRF and the granzymes are exposed to the neutral pH and calciumrich environment of the immune synapse. 4 After binding calcium through their C2 domains, PRF monomers acquire the ability to bind generic lipids in the target cell membrane, 5 and then coalesce into large transmembrane pores that permit the granzymes to access key death substrates in the cytosol. [6][7][8] Although the diverse apoptotic pathways triggered by granzymes have been extensively studied and are now understood in considerable detail, it is only of late that insights into the molecular and cellular functions of PRF have been even partly addressed.In this review, we will re-examine the pathological consequences of PRF deficiency, both in mice and humans. In doing so, important differences in PRF biology between these species will be described. We will discuss the pathogenic effect of a number of recently described missense mutations of human PRF. In particular, although the complete absence of PRF function typically results in an aggressive, fatal immunoregulatory disorder of ea...

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Section: Perforin Biologymentioning

confidence: 99%

Perforin deficiency and susceptibility to cancer

et al. 2010

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“…The protein sequence diverges over a stretch of eight residues close to its 3' end from that reported by Lowrey et al . (15) ; however, this appears to result from two-frame shifts in the latter cDNA sequence. As predicted from DNA blotting experiments, the coding regions of Pfp are entirely contained within a short stretch of the genome (13,15,16).…”

Section: Resultsmentioning

confidence: 84%

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

The Journal of Experimental Medicine

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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.

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“…Besides the putative proteins with similar C2 domain structure in zebrafish, the novel EcOC2 factor is most similar to C2 domains in perforins among the proteins containing C2 domains, because it shares 32% identity with human perforin (Lichtenheld et al, 1988) and mouse perforin (Lowrey et al, 1989). Perforin, as abbreviation of pore-forming protein, is a secreted protein synthesized by activated cytotoxic T lymphocytes and natural killer cells (Uellner et al, 1997).…”

Section: Discussionmentioning

confidence: 99%