Isolation of a novel gene mutated in Wiskott-Aldrich syndrome

Derry, Jonathan M.J.; Ochs, Hans D.; Francke, Uta

doi:10.1016/0092-8674(94)90528-2

Cited by 944 publications

(659 citation statements)

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“…VirG specifically binds to N-WASP even as N-WASP shared amino acid sequences and functional domains with WASP (Derry et al, 1994;Miki et al, 1996). To identify the regions of N-WASP responsible for being recognized by VirG, we generated a series of N-WASP-WASP chimeras by swapping the N-WASP and WASP domains (Fig.…”

Section: Identification Of the N-wasp Domain Required For Interactionmentioning

confidence: 99%

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Neural Wiskott-Aldrich syndrome protein (N-WASP) is the specific ligand for Shigella VirG among the WASP family and determines the host cell type allowing actin-based spreading

et al. 2002

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SummaryShigella, the causative agent of bacillary dysentery, is capable of directing its movement within host cells by forming an actin comet tail. The VirG (IcsA) protein expressed at one pole of the bacterium recruits neural Wiskott-Aldrich syndrome protein (N-WASP), a member of the WASP family, which in turn stimulates actin-related protein (Arp) 2/3 complex-mediated actin polymerization. As all the WASP family proteins induce actin polymerization by recruiting Arp2/3 complex, we investigated their involvement in Shigella motility. Here, we show that VirG binds to N-WASP but not to the other WASP family proteins. Using a series of chimeras obtained by swapping N-WASP and WASP domains, we demonstrated that the specificity of VirG to interact with N-WASP lies in the N-terminal region containing the pleckstrin homology (PH) domain and calmodulin-binding IQ motif of N-WASP. A conformational change in N-WASP was important for the VirG-N-WASP interaction, as elimination of the C-terminal acidic region, which is responsible for the intramolecular interaction with the central basic region of N-WASP, affected the specific binding to VirG. We observed that, in haematopoietic cells such as macrophages, polymorphonuclear leucocytes (PMNs) and platelets, WASP was predominantly expressed, whereas the expression of N-WASP was greatly suppressed. Indeed, unlike Listeria, Shigella was unable to move in macrophages at all, (V) domain, a domain (C) with homology to the actindepolymerizing protein cofilin and, finally, a C-terminal acidic (A) segment (Miki et al., 1996). The C-terminal VCA domain interacts with the actin-related protein (Arp) 2/3 complex after the stimulation of actin polymerization by the complex (Rohatgi et al., 1999). N-WASP exists in two conformations: an inactive form in which the VCA domain is masked, and an active form in which it is exposed to promote actin polymerization by interaction with the Arp2/3 complex. The activation of N-WASP requires Cdc42 or PtdIns(4,5)P2 bound to N-WASP (Miki et al., 1998b;Rohatgi et al., 1999;2000;Prehoda et al., 2000). It has been reported that N-WASP is required for generating the actin tail from motile S. flexneri (Suzuki et al., 1998;Egile et al., 1999). Arp2/3 complex is also required for actin-based motility of Shigella, in which N-WASP stimulates the actin nucleation activity of the Arp2/3 complex in vitro (Egile et al., 1999).In mammalian cells, five WASP family members, N-WASP, WASP and WAVE1-3, have been identified and characterized to date (Suetsugu et al., 1999); however, none of them except N-WASP has been elucidated for involvement in the actin-based motility of Shigella in infected cells. It has been shown that human platelet extracts supported Shigella actin-based motility as added N-WASP in vitro (Egile et al., 1999). Recent reports using N-WASP-deficient mouse embryonic fibroblasts (Lommel et al., 2001;Snapper et al., 2001) confirmed our previous work indicating that N-WASP is required for Shigella motility in mammalian cells (Suzuki et al., 1998). However...

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Section: Identification Of the N-wasp Domain Required For Interactionmentioning

confidence: 99%

“…The expression of WASP is limited to cells of haematopoietic origin such as lymphocytes or platelets (Derry et al, 1994;Stewart et al, 1996;Parolini et al, 1997). In contrast, N-WASP is thought to be ubiquitously expressed (Miki et al, 1996;Suzuki et al, 1998).…”

Section: Human Macrophages Do Not Support Actin-based Motility Of Intmentioning

confidence: 99%

Neural Wiskott-Aldrich syndrome protein (N-WASP) is the specific ligand for Shigella VirG among the WASP family and determines the host cell type allowing actin-based spreading

et al. 2002

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“…23, has been recently cloned, the primary consequences of this molecular defect remain to be elucidated. The deduced sequence of the WAS protein (WASP) defined a novel intracellular protein, but did not reveal a conceivable function for the WASP, although a possible role as transcription factor or signal transduction element [6] has been suggested. The WASP is very likely to be a key regulator of downstream molecules that are important for lymphocyte and platelet function.…”

Section: Introductionmentioning

confidence: 98%

Multiple antigens are altered on T and B lymphocytes from peripheral blood and spleen of patients with Wiskott-Aldrich syndrome

Gerwin¹,

Friedrich²,

Perez‐Atayde

et al. 1996

Clinical and Experimental Immunology

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SUMMARYThe gene for Wiskott-Aldrich syndrome (WAS) has been recently identified and cloned, but our knowledge of downstream events affected in WAS is limited to a few leucocyte cell surface molecules. To identify cell surface molecules whose abnormal expression could contribute to the functional impairment observed in WAS B and T lymphocytes, we studied the expression of a large panel of antigens on peripheral blood lymphoid cells (PBLC) and on isolated lymphocyte subpopulations from the spleen of WAS patients. WAS T lymphocytes from peripheral blood express increased levels of the activation antigens 4F2, CD49d, CD49e, CD53 and the activation/memory marker CD45RO. In the spleen, however, WAS patients have more CD45RA CD4 and CD8 T lymphocytes than normal individuals, suggesting the selective accumulation of presumably naive cells in the WAS spleen. Interestingly, the naive phenotype of the lymphocytes that seem to accumulate in the WAS spleen is confirmed by the absence of increased expression of several activation antigens on their surface, and this correlated with their increased expression of CD43. These lymphocyte abnormalities were accompanied by an abnormal distribution of lymphocyte subsets within the spleen architecture, in particular by the lack of well developed germinal centres and T cell areas. We also found abnormal expression of CD43 and other sialyated proteins such as CDw75 and CD76, whose expression requires the action of specific sialyltransferases. This study shows that the combined impairment in cellular and humoral immunity observed in WAS is the result of multiple molecular abnormalities on the surface of WAS lymphocytes, that in turn might result in recirculation/migration anomalies.

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“…The best known immunodeficiency of this type is the Wiskott-Aldrich syndrome, caused by mutations in WAS, a gene encoding a key regulator of actin in hematopoietic cells 2,3 .…”

Section: Introductionmentioning

confidence: 99%

Cytoskeletal control of B cell responses to antigens

Tolar

2017

Nat Rev Immunol

125

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The actin cytoskeleton is essential for cell mechanics and has increasingly been implicated in the regulation of cell signalling. In B cells, the actin cytoskeleton couples extensively to B cell receptor (BCR) signalling pathways and its defects can either enhance or suppress B cell activation. Recent insights from single-cell imaging and biophysical techniques suggest that actin orchestrates BCR signalling at the plasma membrane through effects on protein diffusion, and that it regulates antigen discrimination through the biomechanics of immune synapses. These mechanical functions also play a role in the adaptation of B cell subsets to specialized tasks during antibody responses.3

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Isolation of a novel gene mutated in Wiskott-Aldrich syndrome

Cited by 944 publications

References 45 publications

Neural Wiskott-Aldrich syndrome protein (N-WASP) is the specific ligand for Shigella VirG among the WASP family and determines the host cell type allowing actin-based spreading

Neural Wiskott-Aldrich syndrome protein (N-WASP) is the specific ligand for Shigella VirG among the WASP family and determines the host cell type allowing actin-based spreading

Multiple antigens are altered on T and B lymphocytes from peripheral blood and spleen of patients with Wiskott-Aldrich syndrome

Cytoskeletal control of B cell responses to antigens

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