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WASP: a key immunological multitasker

Nature Reviews Immunology volume 10, pages 182–192 (2010)Cite this article

Subjects

Key Points

  • Wiskott–Aldrich Syndrome protein (WASP) is an important regulator of the actin cytoskeleton in haematopoietic cells. WASP-deficiency gives rise to the human disease Wiskott–Aldrich Syndrome (WAS), an X-linked primary immunodeficiency. Constitutively active mutations of WASP have recently been described to give rise to a distinct human disease: X-linked neutropenia.

  • WASP activity is attenuated by multiple signalling pathways downstream of surface receptors. Conformational change, phosphorylation and degradation are important mechanisms.

  • Although WASP does not seem to have a key role in haematopoiesis, WASP confers selective advantage for many mature haematopoietic cell types and is emerging as a key regulator of lymphocyte homeostasis.

  • WASP is required for a diverse range of cell functions in innate and adaptive immune cells. These relate both to the role of WASP in cytoskelatal rearrangement and as an intrinsic signalling molecule.

  • Autoimmunity is an important feature of WAS which is poorly understood. Recent studies suggest that defective regulatory T cell function is an important component.

  • Insights into the basic mechanisms of WASP-associated disease are advancing our understanding of immune regulation with wider application, and this allows the potential for future therapeutic benefit.

Abstract

The Wiskott–Aldrich syndrome protein (WASP) is an important regulator of the actin cytoskeleton that is required for many haematopoietic and immune cell functions, including effective migration, phagocytosis and immune synapse formation. Loss of WASP activity leads to Wiskott–Aldrich syndrome, an X-linked disease that is associated with defects in a broad range of cellular processes, resulting in complex immunodeficiency, autoimmunity and microthrombocytopenia. Intriguingly, gain of function mutations cause a separate disease that is mainly characterized by neutropenia. Here, we describe recent insights into the cellular mechanisms of these two related, but distinct, human diseases and discuss their wider implications for haematopoiesis, immune function and autoimmunity.

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Figure 1: Domain structure of Wiskott–Aldrich syndrome protein.
Figure 2: Wiskott–Aldrich syndrome protein and lymphocyte homeostasis.
Figure 3: Wiskott–Aldrich syndrome protein function in immune cells.

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Acknowledgements

A.J.T. is a Wellcome Trust Senior Clinical Fellow. S.B. is supported by the Institute of Child Health Biomedical Research Centre and by the primary Immunodeficiency Association.

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Authors and Affiliations

  1. Molecular Immunology Unit and Centre for Immunodeficiency, University College London Institute of Child Health, 30 Guilford Street, WC1N 1EH, London, UK

    Adrian J. Thrasher & Siobhan O. Burns

  2. Great Ormond Street Hospital for Children National Health Service Trust, Great Ormond Street, WC1N 3JH, London, UK

    Adrian J. Thrasher & Siobhan O. Burns

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  1. Adrian J. Thrasher
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Correspondence to Adrian J. Thrasher.

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DATABASES

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WAS

FURTHER INFORMATION

The Centre for Immunodeficiency homepage

WASPbase

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Glossary

Scaffold protein

A protein that functions as a support to assemble a multiprotein complex.

ARP2–ARP3 complex

A complex composed of seven proteins, including ARP2, ARP3 and ARP complex protein 1 (ARPC1)–ARPC5. On its own, the complex has little activity but, when bound to an ARP2–ARP3-nucleation-promoting factor, it is activated to generate new actin filaments on pre-existing filaments.

Actin filaments

Formed from the nucleation of monomeric actin subunits during remodelling of the cytoskeleton.

Thrombocytopenia

A lower number of circulating platelets than normal, owing to either the failure of production from bone marrow megakaryocytes or increased clearance from the circulation, predominantly in the spleen.

Rho family GTPases

A subfamily of small GTP-binding proteins that have key roles in rearrangement of the cytoskeleton. The nucleotide-bound state of these GTPases is generally regulated by guanine-nucleotide exchange factors (GEFs), which catalyse GDP–GTP exchange, and GTPase-activating proteins, which facilitate the hydrolysis of the bound GTP. Activation, by extracellular signals through various receptors, results in translocation to the plasma membrane thereby localizing their activity to discrete sites in the cell.

Calpain

One of a group of Ca2+-activated cytoplasmic proteases that are found in many tissues and that hydrolyse various endogenous proteins, including neuropeptides and cytoskeletal proteins, as well as proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses are known: one with high Ca2+ sensitivity and one with low Ca2+ sensitivity.

Podosome

An adhesion structure that is found in various malignant cells and in some normal cells, including macrophages and osteoclasts. Podosomes are small (0.5 μm diameter) structures comprising an actin core surrounded by a ring containing typical focal-adhesion proteins, such as vinculin and paxillin.

Aorta–gonad–mesonephros region

An embryonic site in which the development of definitive haematopoietic stem cells (HSCs) occurs. It comprises the aorta and developing reproductive and excretory (mesonephros) systems. In this haematogenic site, HSCs are concentrated in the aortic region.

X-chromosome inactivation

In females, a single, randomly selected X chromosome is inactivated during early embryogenesis to avoid an imbalance of X-linked genes. This process is controlled by the XIST gene, which produces a large non-protein-encoding RNA that triggers widespread gene silencing on the same X chromosome. If one X chromosome encodes a gene that impairs cell growth or survival, development of cells with the non-silenced normal chromosome is favoured. This is known as apparent non-random X-chromosome inactivation.

Aneuploidy

The occurrence of one or more extra or missing chromosomes, which leads to an unbalanced chromosome complement.

Immune synapse

A discrete contact site classically formed at the point of contact between an antigen-presenting cell (APC) and a T cell. Similar synapses have been described in other immune cells such as natural killer or cytotoxic T cells, where the synapse is formed with a target cell. It is important in establishing cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.

Marginal zone

A region at the border of the white pulp of the spleen.

Marginal zone B cell

A mature B cell that is enriched in the marginal zone of the spleen. They recognize antigen through semi-invariant receptors, which stimulates their rapid differentiation into antibody-secreting cells. They are thought to be important for host defence against circulating blood-borne pathogens.

Integrin

A member of a large family of transmembrane proteins that traverse the plasma membrane as heterodimers of α- and β-subunits. They have an important role in mediating the interaction of cells with extracellular matrix components, such as fibronectin, and in mediating intracellular cytoskeleton arrangement.

Invariant NKT (iNKT) cell

A lymphocyte that expresses a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα (joining) gene segment to yield T cell receptor α-chains with an invariant sequence. Typically, these cells co-express cell surface markers that are encoded by the natural killer (NK) locus, and they are activated by recognition of CD1d molecules presenting glycolipid antigens.

Lamellipodia

Thin sheet-like processes, which extend at the leading edge of moving cells in an actin-dependent manner, promoted by the Rho family GTPase RAC1.

Respiratory burst

A large increase in oxygen consumption and reactive oxygen species generation that accompanies the exposure of neutrophils to microorganisms and/or inflammatory mediators.

Eczematous skin disease

A clinical process that is associated with severe pathological changes to the skin, which is characterized by redness, oozing, crusting and loss of pigmentation. Histologically, it is characterized by epidermal changes of intracellular oedema, spongiosis or vesiculation.

Antinuclear antibodies

Heterogeneous autoantibodies against one or more antigens present in the nucleus, including chromatin, nucleosomes and ribonuclear proteins. Antinuclear antibodies are found in association with many different autoimmune diseases.

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Thrasher, A., Burns, S. WASP: a key immunological multitasker. Nat Rev Immunol 10, 182–192 (2010). https://doi.org/10.1038/nri2724

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