Apoptosis induced by the lymphocyte effector molecule perforin

doi:10.1016/j.coi.2007.04.007

Current Opinion in Immunology

Volume 19, Issue 3, June 2007, Pages 339-347

https://doi.org/10.1016/j.coi.2007.04.007 Get rights and content

Recent progress has been made in discovering structure/function relationships of the cytotoxic lymphocyte pore-forming protein — perforin — and its role in immune regulation. Long recognized as a key component of the granule exocytosis mechanism of lymphocyte-mediated apoptosis and in host defence against a variety of pathogens and tumors, more recent attention has focused upon mutations of the perforin gene in some patients with hemophagocytic lymphohistiocytosis. This clinical picture has prompted further work to uncover the molecular structure of perforin and to define its precise role in immune regulation and immunopathology.

Introduction

Cytotoxic lymphocytes, including cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, recognize virus-infected or transformed cells and destroy them through perforin-dependent and/or death receptor–death ligand pathways. As such, these pathways represent fundamental mechanisms of both immune surveillance and immunoregulation. Cytotoxic lymphocyte granules contain perforin and many additional pro-apoptotic proteins that are co-secreted to kill target cells. Perforin is encoded by a single copy gene, is highly conserved from fish to primates, and is crucial for the function of the other granule constituents such as granzymes involved in triggering caspase-dependent and caspase-independent target cell death following the formation of an immunological synapse. Mutations and polymorphisms in this effector pathway have been described in mice and humans, and interestingly the phenotypes principally involve defective immune surveillance and/or derangement of lymphoid homeostasis. This review summarizes the most recent and rapid developments in our understanding of the molecular basis of the granule exocytosis effector pathway and its pathophysiological importance.

Section snippets

Developments in the molecular biology of perforin

Granule exocytosis occurs following cytotoxic lymphocyte–target cell synapse formation and involves the polarized trafficking of secretory granules towards the synapse. Granule fusion with the plasma membrane results in the release of perforin and pro-apoptotic serine proteases (granzymes) as well as many other molecules including granulysin and chemokines. Perforin is a pore-forming protein of ∼67 kDa, the expression of which is regulated during lymphocyte differentiation by receptor activation

Developments in the pathophysiology of perforin

Loss of perforin function in mice is associated with immune dysregulation and impaired cytotoxicity, clearly demonstrating the crucial role perforin has as an immune effector molecule [27, 28, 29]. Perforin-deficient mice are viable and healthy under specific pathogen-free conditions, however compromised cellular cytotoxicity is observed upon challenge with certain viruses and they display defects in tumor and transplant rejection. In humans, congenital perforin deficiency accounts for many of

Conclusions

In summary, although there is now no doubt regarding the pivotal importance of lymphocyte perforin in immune response and immune regulation, recent progress in the study of perforin pathophysiology has been relatively slow. In particular, the important discoveries that regulatory lymphocytes express and utilize perforin and that granzyme B might contribute to the death of Th2 cells raise the possibility that interpreting the biology from perforin- or granzyme-deficient hosts might be more

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

PB is supported by a Cancer Research Institute Pre-doctoral Emphasis in Tumor Immunology Scholarship. MJS and JAT are supported by Research Fellowships and a Program Grant from the National Health and Medical Research Council (NHMRC) of Australia. IV receives a career development award from NHMRC. We also thank our colleagues in the Cancer Immunology Program and our collaborators for contributions to many of the findings referred to in this review.

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Perforins on the other hand, are secreted by the cytotoxic T lymphocytes and Natural Killer cells (NK cells) (Podack & Konigsberg, 1984). Perforins generate pores on the virus-infected cells and cancerous host cells (Bolitho, Voskoboinik, Trapani, & Smyth, 2007). Owing to its large pore size, perforins assist in delivering the pro-apoptotic proteases, granzymes, into the target host cells leading to its programmed cell-death (Bird et al., 2005; Metkar et al., 2015; Voskoboinik, Smyth, & Trapani, 2006).
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Apoptosis induced by the lymphocyte effector molecule perforin

Introduction

Section snippets

Developments in the molecular biology of perforin

Developments in the pathophysiology of perforin

Conclusions

References and recommended reading

Acknowledgements

Structure

J Biol Chem

Blood

Cell

J Cell Biol

Blood

Mol Biol Cell

Cell Death Differ

J Immunol

Immunity

Immunol Res

J Cell Biol

Trends Immunol

Leukemia

J Virol

Nat Rev Immunol

Hum Mutat

Immunity

J Exp Med

J Virol

J Immunol

Structure and function of human perforin

Nature

The C2 domain calcium-binding motif: structural and functional diversity

Protein Sci

Crystal structure of the cytosolic C2A–C2B domains of synaptotagmin III. Implications for Ca+2-independent SNARE complex interaction

J Cell Biol

Perforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipid-binding C2 domain

EMBO J

Surface cathepsin B protects cytotoxic lymphocytes from self-destruction after degranulation

J Exp Med

Cytotoxic T lymphocytes from cathepsin B-deficient mice survive normally in vitro and in vivo after encountering and killing target cells

J Biol Chem

Granzyme-mediated cytotoxicity does not involve the mannose 6-phosphate receptors on target cells

J Biol Chem

Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells

Mol Cell Biol

Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin

Mol Cell Biol

Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis

Immunity

The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death

Mol Cell

Granzyme M mediates a novel form of perforin-dependent cell death

J Biol Chem

Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin

J Biol Chem

A novel domain in adenovirus L4-100K is required for stable binding and efficient inhibition of human granzyme B: possible interaction with a species-specific exosite

Mol Cell Biol

Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice

Nature

Crystal structure of the cytosolic C2A–C2B domains of synaptotagmin III. Implications for Ca⁺²-independent SNARE complex interaction