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Perforin and granzymes: function, dysfunction and human pathology

Key Points

  • This article reviews recent advances in the structural, cellular and clinical aspects of perforin and granzyme biology.

  • It describes the cellular and biochemical mechanisms that are responsible for protecting cytotoxic T lymphocytes and natural killer cells from endogenous cytotoxic perforin and granzymes.

  • Structural studies have shown evolutionary conservation and similar mechanisms of pore formation by perforin-like family proteins and the bacterial virulence factors cholesterol-dependent cytolysins.

  • Perforin and granzymes synergize to mediate apoptosis of target cells: pro-apoptotic granzymes diffuse through perforin pores on the plasma membrane of the target cell.

  • Granzymes have various cytotoxic and non-cytotoxic mechanisms of action and have roles in inflammation and cancer.

  • A group of autosomal-recessive, immune-mediated diseases — known as perforinopathies — are discussed. These are caused by insufficient perforin delivery to the immunological synapse, due either to perforin mutations or to impaired granule exocytosis.

  • A common perforin polymorphism, Ala91Val — which predisposes carriers to immunological disorders — is highlighted.

Abstract

A defining property of cytotoxic lymphocytes is their expression and regulated secretion of potent toxins, including the pore-forming protein perforin and serine protease granzymes. Until recently, mechanisms of pore formation and granzyme transfer into the target cell were poorly understood, but advances in structural and cellular biology have now begun to unravel how synergy between perforin and granzymes brings about target cell death. These and other advances are demonstrating the surprisingly broad pathophysiological roles of the perforin–granzyme pathway, and this has important implications for understanding immune homeostasis and for developing immunotherapies for cancer and other diseases. In particular, we are beginning to define and understand a range of human diseases that are associated with a failure to deliver active perforin to target cells. In this Review, we discuss the current understanding of the structural, cellular and clinical aspects of perforin and granzyme biology.

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Figure 1: Interaction of a cytotoxic lymphocyte with a target cell.
Figure 2: Structural transitions of cholesterol-dependent cytolysins and perforin.
Figure 3: Perforin pore formation in action.

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Acknowledgements

I.V. and J.C.W. are supported by fellowships from the National Health and Medical Research Council of Australia (NHMRC). I.V., J.C.W. and J.A.T. are supported by project grants from the NHMRC. J.C.W. is supported by the Australian Research Council (ARC) and he acknowledges the support of an ARC Federation fellowship. J.A.T. is supported by a programme grant from the NHMRC. The authors thank the many members of their laboratories, especially J. A. Lopez and A. J. Brennan, and their collaborators, especially H. Saibil, M. A. Dunstone, R. H. P. Law and N. Lukoyanova, for their contributions to many of the findings discussed in this Review.

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Glossary

Perforinopathies

A range of human immune-mediated disorders that are caused by impaired perforin delivery or function.

Toxic epidermal necrolysis

A rare life-threatening skin disease in which the dermis detaches from the epidermis. This disease often leads to sepsis and death. It is also known as Lyell syndrome; one of its forms is called Stevens–Johnson syndrome.

Microtubule-organizing centre

(MTOC). An intracellular structure from which microtubules originate. In cytotoxic lymphocytes, the MTOC moves towards the immunological synapse.

Wiskott–Aldrich syndrome

A life-threatening X-linked immunodeficiency that is caused by mutations in the gene encoding the Wiskott–Aldrich syndrome protein. The condition is characterized by thrombocytopaenia with small platelets, eczema, recurrent infections caused by immunodeficiency and an increased incidence of autoimmune manifestations and malignancies.

Emperitosis

A process by which a granzyme B-expressing cytotoxic lymphocyte is taken up by the target cell and killed by apoptosis.

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Voskoboinik, I., Whisstock, J. & Trapani, J. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol 15, 388–400 (2015). https://doi.org/10.1038/nri3839

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