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Perforin and granzymes: function, dysfunction and human pathology
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Journal Article
Perforin and granzymes: function, dysfunction and human pathology
2015
Overview
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.
Cytotoxic lymphocytes recognize virus-infected and transformed cells and kill them by apoptosis. Recent studies on the structural and cellular biology of the key mediators of this cytotoxicity — perforin and granzymes — have advanced our understanding of their mechanisms of action, their regulation and the pathophysiological consequences of impaired cytotoxicity.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
