Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation. Immunobiology 214(9-10):778-790

Centre for Immunodeficiency, UCL Institute of Child Health, London, UK.
Immunobiology (Impact Factor: 3.04). 08/2009; 214(9-10):778-90. DOI: 10.1016/j.imbio.2009.06.009
Source: PubMed


Regulation of the actin cytoskeleton is crucial for many aspects of correct and cooperative functioning of immune cells, such as migration, antigen uptake and cell activation. The Wiskott-Aldrich Syndrome protein (WASp) is an important regulator of actin cytoskeletal rearrangements and lack of this protein results in impaired immune function. This review discusses recent new insights of the role of WASp at molecular and cellular level and evaluates how WASp deficiency affects important immunological features and how defective immune cell function contributes to compromised host defence.

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Available from: Gerben Bouma
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    • "Importantly, WIP and WASP are essential for the assembly and turnover of podosomes, actin-rich adhesions implicated in the invasion and matrix remodelling of professional migratory cells such as macrophages, dendritic cells and osteoclasts (Calle et al., 2004b; Chabadel et al., 2007). Macrophages and dendritic cells from WAS patients fail to form podosomes and this is likely to be a major contributing factor to the defective trafficking and immune surveillance of these cells that are characteristic of this disease (Bouma et al., 2009; Burns et al., 2004; Jones et al., 2002; Thrasher, 2002). Although the ability of WIP to protect WASP from proteolytic degradation is vital for WASP function in podosome formation, WIP has also been shown to contribute directly to the regulation of these structures, targeting WASP to sites of podosome assembly (Chou et al., 2006). "
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    ABSTRACT: Podosomes are integrin-containing adhesion structures commonly found in migrating leukocytes of the monocytic lineage. The actin cytoskeletal organisation of podosomes is based on a WASP-Arp2/3 mediated mechanism. WASP also associates with a second protein, WIP, where they co-localise in podosome cores. Here we report for the first time that WIP can be phosphorylated on tyrosine residues and that tyrosine phosphorylation of WIP is a trigger for release of WASP from the WIP-WASP complex. Using a knockdown approach together with expression of WIP phosphomimics, we show that in the absence of WIP-WASP binding, cellular WASP is rapidly degraded, leading to disruption of podosomes and a failure of cells to degrade an underlying matrix. In the absence of tyrosine phosphorylation, the WIP-WASP complex remains intact and podosome lifetimes are extended. A screen of candidate kinases and inhibitor-based assays identified Bruton's tyrosine kinase as a regulator of WIP tyrosine phosphorylation. We conclude that tyrosine phosphorylation of WIP is a critical regulator of WASP stability and function as an actin nucleation promoting factor.
    Full-text · Article · Nov 2014 · Journal of Cell Science
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    • "Cell motility is essential during embryonic development as well as throughout adult life for proper organogenesis, woundhealing and immune system function (Bouma et al., 2009). However, cell motility can be detrimental when it contributes to cancer cell spreading. "
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    ABSTRACT: Border Cells in the Drosophila ovaries are a useful genetic model for understanding the molecular events underlying epithelial cell motility. During stage 9 of egg chamber development they detach from neighboring stretched cells and migrate between the nurse cells to reach the oocyte. RNAi screening allowed us to identify the dapc1 gene as being critical in this process. Clonal and live analysis showed a requirement of dapc1 in both outer border cells and contacting stretched cells for delamination. This mutant phenotype was rescued by dapc1 or dapc2 expression. Loss of dapc1 function was associated with an abnormal lasting accumulation of β-catenin/Armadillo and E-cadherin at the boundary between migrating border and stretched cells. Moreover, β-catenin/armadillo or E-cadherin downregulation rescued the dapc1 loss of function phenotype. Altogether these results indicate that Drosophila Apc1 is required for dynamic remodeling of β-catenin/Armadillo and E-cadherin adhesive complexes between outer border cells and stretched cells regulating proper delamination and invasion of migrating epithelial clusters.
    Full-text · Article · May 2012 · Developmental Biology
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    • "WASP contains several functional domains, including an N-terminal enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) homology 1 (EVH1) domain (also known as WASP homology 1 (WH1) domain), a GTPase-binding domain (GBD), a proline-rich region (PRR), and a C-terminal verproline/cofilin/acidic (VCA) domain. The presence of multiple domains suggests that WASP recruits various kinds of adaptor molecules, protein tyrosine kinases, and actin-binding proteins, and therefore connects tyrosine kinase signaling to cellular motility devices driven by actin polymerization [8], [9]. "
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    ABSTRACT: While Wiskott-Aldrich syndrome protein (WASP) plays critical roles in TCR signaling as an adaptor molecule, how it transduces innate immune signals remains to be elucidated. To investigate the roles of WASP in innate immune cells, we established bone marrow-derived macrophage (BMDM) cell lines from WASP15 transgenic (Tg) mice overexpressing the WASP N-terminal region (exons 1-5). Upon LPS stimulation, WASP15 Tg BMDM cell lines produce lower levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-12p40 than the wild-type BMDM cell line. In addition, the production of nitric oxide by WASP15 Tg BMDM cells in response to LPS and IFN-γ was significantly impaired. Furthermore, we uncovered that the WASP N-terminal domain associates with the Src homology (SH) 3 domain of Bruton's tyrosine kinase (Btk). Overexpression of the WASP N-terminal domain diminishes the extent of tyrosine phosphorylation of endogenous WASP in WASP15 Tg BMDM cells, possibly by interfering with the specific binding between endogenous WASP and Btk during LPS signaling. These observations strongly suggest that the interaction between WASP N-terminal domain and Btk plays important roles in the LPS signaling cascade in innate immunity.
    Full-text · Article · Jan 2012 · PLoS ONE
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