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Wasp in immune-system organization and function

Nature Reviews Immunology volume 2, pages 635–646 (2002)Cite this article

Key Points

  • Wiskott–Aldrich syndrome (WAS) is a rare X-linked disease that is characterized by immune dysregulation and micro-thrombocytopaenia.

  • WAS protein (WASp) is a haematopoietic-restricted member of a family of proteins that transduce signals from the cell surface to the actin cytoskeleton.

  • When activated by the Rho GTPase Cdc42, WASp binds to the cytoskeletal-organizing complex Arp2/3, which initiates polymerization of actin and formation of a branching network of filaments.

  • WASp has many effects on the immune system and participates in antigen-receptor signalling, phagocytosis and cell migration.

  • Many of the defects of WAS might be attributable to abnormal cell transport and cell–cell interactions.

Abstract

The regulation of many immunological events depends on systems that mediate dynamic actin reorganization in response to signals from the cell membrane. The Wiskott–Aldrich syndrome protein (WASp) is the founding member of a family of proteins that have emerged as crucial effectors of Rho GTPases and activators of the cytoskeletal-organizing complex Arp2/3. Now, WASp has been shown to be intimately involved in many pathways that influence the function of the immune system. Disturbances in these systems result in the complex immunodysregulation of Wiskott–Aldrich syndrome.

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Figure 1: Cytoskeletal structures in human dendritic cells.
Figure 2: Assembly of the WASp signalling complex.
Figure 3: Autoinhibition of WASp.
Figure 4: WASp is necessary for podosome formation in dendritic cells.

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Acknowledgements

I would like to thank Professors G. Jones and C. Kinnon for many helpful discussions; S. De Noronha, S. Barker and S. Burns for confocal images; and S. Ballard for help with the preparation of this manuscript. I am also grateful to the Wellcome Trust, the Primary Immunodeficiency Association and the European Union 5th Framework for continued funding.

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Authors and Affiliations

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

    Adrian J. Thrasher

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DATABASES

Entrez

Listeria monocytogenes

FlyBase

Wasp

InterPro

DH

PH

SH3

WH1

WH2

LocusLink

ARP2

ARP3

BTK

CD2

CD28

CD43

CD69

Cdc42

CR3

CSF1

FcγR

Fyn

GRB2

ICAM1

interleukin-2

intersectin-2

IRSp53

JAM1

LFA1

Lck

MCP1

MIP1

moesin

Nck

N-WASp

PAK1

paxillin

profilin

PSTPIP

PTP-PEST

Rac1

Rac2

RhoA

RhoB

SCAR1

SCAR2

SCAR3

SDF1

talin

TC10

TCL

thymosin-β4

VASP

Vav

vinculin

WASp

WIP

ZAP70

OMIM

WAS

XLT

<i>Saccharomyces</i> Genome Database

verprolin

Swiss-Prot

GFP

Glossary

THROMBOCYTOPAENIA

A reduced number of circulating platelets, owing to either the failure of production from bone-marrow megakaryocytes or increased clearance from the circulation, predominantly in the spleen. Thrombocytopaenia with small platelet volume is known as micro-thrombocytopaenia.

IMMUNOLOGICAL SYNAPSE

A structure that is formed on the cell surface between a T cell and an antigen-presenting cell or a target cell; also known as a supra-molecular activation cluster. Important molecules that are involved in T-cell activation — including the T-cell receptor, many signal-transduction molecules and molecular adaptors — accumulate at this site. Mobilization of the actin cytoskeleton of the cell is required for synapse formation.

CAPPING

The formation of an asymmetric patch of molecules — including adhesion molecules, and T-cell receptors or B-cell receptors — on the lymphocyte surface after stimulation.

X-INACTIVATION

In females, a single, randomly selected X-chromosome is inactivated in each cell during early embryogenesis to avoid an imbalance of X-linked genes. This process is controlled by the Xist gene, which transcribes to a large non-protein-encoding RNA and triggers widespread gene silencing on the same X-chromosome. In some cases, mutations in Xist result in inactivation of only one of the X-chromosomes so that the pattern is non-random. If one of the X-chromosomes encodes a gene that has detrimental effects on cell growth or survival, development of cells with the normal chromosome will be favoured. This is known as apparent non-random X-inactivation.

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Thrasher, A. Wasp in immune-system organization and function. Nat Rev Immunol 2, 635–646 (2002). https://doi.org/10.1038/nri884

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