WAS (Wiskott-Aldrich syndrome)

Description	502 amino acids; 54 kDa; consists of an N-terminal Ena-VASP homology domain 1 (EVH1), a basic domain, a GTPase binding domain (GBD), polyproline domain and the C-terminal domain comprising of a cluster of verprolin homology (V), central (C) and acidic regions (A) (the VCA domain).
Expression	WASP is consitutively expressed in all haematopoietic stem-cell-derived lineages, except in mature red blood cells. Neural WASP (N-WASP) and WASP family verprolin homologous protein 1 (WAVE1), WAVE2 and WAVE3 are more widely expressed.
Localisation	WASP is located in the cytoplasmic compartment with highest density along the cell membrane.
	Figure 1: WASP and lymphocyte homeostasis. Dependence on WASP for homeostatic regulation varies with cell lineage and stage of maturity. Early stages of B cell development proceed normally in the bone marrow but homeostatic defects of peripheral subpopulations are apparent. The same is true for peripheral T-cells; and in humans with revertant WASP expression confers a survival advantage to these populations. Picture courtesy of Dr Siobhan Burns.
Function	WASP family members function as scaffold proteins, transducing a wide range of signals from proteins or membranes to mediate dynamic changes in the actin cytoskeleton. A lack of WASP results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration. WASP function in Haematopoietic system WASP is expressed by all leukocytes, but dependence on WASP for homeostatic regulation varies with cell lineage and stage of maturity. WASP is required for the development and survival of mature lymphoid cell lineages but myeloid cell lineages that express normal WASP levels show little or no selective advantage. WASP function in T cells T cell development appears normal in WAS patients but the circulating lymphocyte number is reduced and progressively declines throughout childhood. There is decreased thymic output and lowered peripheral T cell survival rates. T cell proliferation in response to TCR stimulation is defective in vitro, and the clonal distribution of TCR β -chain families is usually disturbed. The morphology of WASP-deficient T cells is disturbed with fewer microvillus-like surface projections. They are less able to proliferate in response to various stimuli because WASP is normally recruited to the immunological synapse. In the absence of WASP, the localised assembly of filamentous actin and recruitment of other immunological synapse proteins is impaired in response to TCR stimulation. WASP function in B cells WASP-deficient B cells have defective polarisation, spreading, aggregation and migration in response to CXCL13. Marginal Zone B cells are reduced and they fail to migrate in response to sphingosine-1-phosphate, which is crucial for marginal zone homing. This is consistent with a defect in response to polysaccharide antigens. The abnormal regulation of the actin cytoskeleton in B cells may be important for development of autoimmunity. WASP function in NK cells In the absence of WASP, NK cell cytotoxicity is impaired as immune synapse formation relies upon actin polymerisation. There is also defective signal transduction and poor intercellular interactions, particularly with dendritic cells. WASP function in Invariant NKT cells Invariant NKT (iNKT) cells express both NK- and T-cell receptors; and recognise lipid antigens via the non-classical class I MHC molecule CD1d. They are thought to be important in initial response to infection, protection from autoimmunity and clearance of malignant cells. WAS patients have reduced numbers of iNKT cells which also secrete less cytokine when stimulated. WASP function in innate immune cells WASP-deficient myeloid lineage cells have impaired phagocytosis, a process which relies upon quick and regulated de novo actin polymerisation. In addition, monocytes, macrophages, DCs and osteoclasts lack ability to assemble podosomes in the absence of WASP, resulting in severe defects in adhesion and motility. Efficient cell migration also requires interactions involving integrins. In WASP-deficient human and mouse neutrophils, β2 integrin clustering is defective resulting in impaired integrin-dependent functions that range from adhesion and migration to degranulation and activation of the respiratory burst. Autoimmunity Abnormal Treg have been implicated in the onset of autoimmunity in WAS. WASP-deficient Treg cells fail to proliferate normally in response to TCR simulation and their suppressive activity is impaired in vitro. Dysregulation of B cell tolerance is supported by the presence of autoantibodies in WAS patients and in both WASP null and phosphorylation mutant mice.
	Figure 2: WASP protein function in immune cells. WASP is important in regulating the polymerisation of new branched actin filaments and has a role in processes such as phagocytosis, cell motility and signalling. BCR, B cell receptor; NK, natural killer; TCR, T cell receptor. Picture courtesy of Dr Siobhan Burns.

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