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  • Review Article
  • Published:

SNAREing immunity: the role of SNAREs in the immune system

Nature Reviews Immunology volume 6, pages 919–929 (2006)Cite this article

Key Points

  • All functions of immune cells rely on vesicle-trafficking pathways for the transport and delivery of proteins and membranes to the cell surface or other destinations. At each trafficking step, vesicles bud from one membrane and must dock and fuse with their target membrane.

  • The 38 known members of the SNARE (soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptor)-protein family participate in vesicle docking and membrane fusion throughout trafficking pathways in eukaryotic cells. Members of this family have a common α-helical SNARE motif that binds SNARE proteins to each other in functional complexes.

  • Usually, pairing of an R-SNARE on the vesicle, with a cognate Q-SNARE complex on the target membrane forms a trans-SNARE complex that bridges the membranes and drives them together to fuse.

  • SNARE expression can vary between cells, and in some cells, such as macrophages, the expression of SNAREs is regulated during cell activation.

  • Individual SNARE-family members are differentially distributed on compartments and vesicles and these locations can vary between cell types. The locations of SNAREs can be used experimentally to map or define trafficking pathways.

  • In granulocytes, SNARE proteins that are associated with different secretory granules allow for the selective release of granule contents and immune mediators.

  • In macrophages, a constitutive exocytic pathway transports newly synthesized cytokines to the cell surface in two transport steps, for which the functional trans-SNARE complexes have been defined. The cytokine is first delivered to the recycling endosome, which then fuses with the cell surface at sites of phagocytosis both to release cytokine and expand the phagocytic cup.

  • During phagocytosis in macrophages, different organelles are recruited and fuse in a SNARE-dependent manner to expand and modify the phagosome. The functional trans-SNARE complexes in most cases have not yet been defined.

  • In T cells, SNAREs regulate membrane fusion and the delivery of receptors to immunological synapses for antigen presentation.

  • Mutations in SNAREs and SNARE-associated proteins can be the cause of the defective immune responses that are seen in some genetic diseases.

Abstract

The trafficking of molecules and membranes within cells is a prerequisite for all aspects of cellular immune functions, including the delivery and recycling of cell-surface proteins, secretion of immune mediators, ingestion of pathogens and activation of lymphocytes. SNARE (soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptor)-family members mediate membrane fusion during all steps of trafficking, and function in almost all aspects of innate and adaptive immune responses. Here, we provide an overview of the roles of SNAREs in immune cells, offering insight into one level at which precision and tight regulation are instilled on immune responses.

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Figure 1: Intracellular trafficking pathways require multiple steps of membrane fusion.
Figure 2: Functional example of SNARE-mediated granule fusion.
Figure 3: Macrophage SNARE-mediated pathway for cytokine secretion and phagocytosis.

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Acknowledgements

We wish to thank colleagues for helpful discussions and criticisms and to apologize to those whose work we could not cite owing to space limitations. Relevant research by J.L.S. and colleagues is supported by funding from the National Health and Medical Research Council of Australia and the US National Institutes of Health.

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  1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, Queensland, Australia

    Jennifer L. Stow, Anthony P. Manderson & Rachael Z. Murray

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  1. Jennifer L. Stow
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Correspondence to Jennifer L. Stow.

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Glossary

Endocytic pathway

The pathway by which proteins and lipids from the cell surface and extracellular milieu are internalized into membrane-bound compartments and either recycled back to the surface or targeted to lysosomes for degradation. The phagosomal pathway is highly connected with the endocytic pathway.

Exocytic pathway

The pathway by which proteins are transported to their final cellular or extracellular destination. Generally, newly synthesized proteins are transported through the endoplasmic reticulum to the Golgi and packaged into vesicles that are transported to, and fuse with, the plasma membrane.

Tethering factors

These have restricted subcellular localization and act as molecular 'bridges' to link opposing membranes before SNARE-complex formation.

Tetanus toxin

A clostridial neurotoxin that irreversibly cleaves and inactivates the R-SNAREs VAMP1, VAMP2 and VAMP3.

Trans-SNARE complex

Four-α-helical bundle that is formed by intertwining a single R-SNARE helix with three helices of the Q-SNARE complex. The trans-SNARE complex forms transiently to bridge two membranes and draws them together for fusion.

SNARE motif

Soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptor motif. ∼60-amino-acid α-helical domain characteristic of the members of the SNARE-protein family. This motif functions in SNARE–SNARE protein interactions.

Cis-SNARE complex

A fully assembled post-fusion SNARE complex located in the target membrane before its disassembly.

α-Granules

Large filamentous granules found in platelets, containing growth factors, coagulation proteins, integrins and chemokines.

Dense granules

Electron-dense platelet granules containing serotonin, ADP and divalent cations.

Lysosomes

Acidic organelles that contain hydrolytic enzymes that are responsible for the degradation of a range of macromolecules. In some cell types, lysosomes have specialized functions — for example in antigen-presenting cells, this compartment is responsible for the production of antigenic peptides for presentation on MHC molecules. In platelets, lysosomes undergo regulated secretion to release enzymes into the extracellular milieu for clot formation.

Azurophilic granules

Large storage granules that are present in neutrophils and contain several acid hydrolases and anti-microbial products (such as myeloperoxidase, lysozyme, cathepsin G and defensins). They act as primary lysosomes during the degradation of foreign organisms.

Specific granules

Specific granules are found in neutrophils and eosinophils but their content is different: in neutrophils, they contain several antibiotic substances (such as collagenase, heparinase, lactoferrin and cytochrome b), whereas eosinophil granules (also known as secondary granules) have the characteristics of lysosomes.

Gelatinase (tertiary) granules

Found in neutrophils, gelatinase granules contain gelatinase, lysozyme and metalloproteases.

Secretory vesicles

Small membrane-bound vesicles that are present in all granulocyte populations, although their cargo seems to differ. In eosinophils, they shuttle the contents of granules (such as CCL5 and TGFβ) to the plasma membrane for secretion in a process known as piecemeal degranulation, whereas neutrophil secretory vesicles contain adhesion receptors.

Phagosome

A membrane-encapsulated compartment that arises from the ingestion of a foreign particle such as a bacterium. The phagosome then matures by sequential fusion with early and late endosomes and, ultimately, lysosomes to form the microbicidal phagolysosome, where pathogens are killed and degraded.

Late endosome

In the endocytic pathway, late endosomes are situated after early endosomes and deliver endocytosed macromolecules to lysosomes for degradation.

Crystalloid granule

The central storage granule of eosinophils, which contains anti-microbial/parasitic agents (such as major basic protein, erythropoietin, peroxidase and gelatinase) and several cytokines and chemokines.

Small granule

An eosinophilic granule containing degradative enzymes such as the active form of arylsulphatase B and acid phosphatase.

Recycling endosome

A post-early-endosome component of the recycling pathway through which internalized molecules recycle to the cell surface.

Phagocytic cup

A structure that forms around large particles during the process of phagocytosis. The formation of the phagocytic cup requires additional membrane at the site of particle binding, which is achieved by the fusion of internal compartments such as recycling endosomes and endoplasmic reticulum.

Dominant negative

Dominant-negative mutant SNARE proteins compete with the wild-type SNARE for binding to its cognate SNARE partners, but without a membrane anchor they act to inhibit fusion.

Early endosome

The first organelle in the endocytic pathway to receive internalized proteins and lipids from the cell surface.

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell. Important molecules that are involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Immunological synapses are now known to form also between other types of immune cell: for example, between dendritic cells and natural killer cells.

Cross presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

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Stow, J., Manderson, A. & Murray, R. SNAREing immunity: the role of SNAREs in the immune system. Nat Rev Immunol 6, 919–929 (2006). https://doi.org/10.1038/nri1980

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