Novel membrane cell projection defects in Wiskott-Aldrich syndrome B cells

Andreu, Núria; Aran, Josep M.; Fillat, Cristina

doi:10.3892/ijmm.20.4.445

Cited by 6 publications

(7 citation statements)

References 28 publications

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“…In addition, they have defective actin cytoskeletons, fail to make filopodia, are less motile, spread less, and aggregate less than normal B cells on Ab-coated surfaces. 115,[118][119][120] This cytoskeletal defect could be the cause of the decreased migra-tion of WAS-deficient B cells in vitro and in vivo and the poor homeostasis of peripheral B cells, mostly MZ B cells. [115][116][117] Primary B cells from WAS patients and WASp −/− mice proliferate normally and have normal signaling downstream of the B cell receptor.…”

Section: Was B Cellsmentioning

confidence: 99%

Wiskott‐Aldrich syndrome: a comprehensive review

Massaad

Ramesh

Geha

2013

Annals of the New York Academy of Sciences

305

264

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Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity and malignancies. The disease is caused by mutations in the WAS gene expressed exclusively in hematopoietic cells. WAS protein (WASp) is a multidomain protein that exists in complex with several partners that play important roles in its function. WASp belongs to a family of proteins that relay signals from the surface of the cell to the actin cytoskeleton. Mutations in the WAS gene have various effects on the level of WASp, which, in turn, correlates with the severity of the disease. In addition to WAS, mutations in the WAS gene can result in the mild variant X-linked thrombocytopenia, or in X-linked neutropenia, characterized by neutropenia with myelodysplasia. The absence of functional WASp leads to a severe clinical phenotype that can result in death if not diagnosed and treated early in life. The treatment of choice with the best outcome is hematopoietic stem cell transplantation, preferably from a matched related donor.

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Section: Was B Cellsmentioning

confidence: 99%

Wiskott‐Aldrich syndrome: a comprehensive review

Massaad

Ramesh

Geha

2013

Annals of the New York Academy of Sciences

305

264

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“…EBV transformed cell lines have defective actin polymerization [142]. B cells have defective polarisation, spreading, aggregation and migration in response to CXCL13 [143,144], and are defective in producing filopodia in response to bradykinin [145]. Specific subsets of B cells are also abnormal.…”

Section: B Cell Defectsmentioning

confidence: 99%

The Wiskott-Aldrich Syndrome: The Actin Cytoskeleton and Immune Cell Function

Blundell¹,

Worth

Bouma³

et al. 2010

Disease Markers

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Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by immune dysregulation, microthrombocytopaenia, eczema and lymphoid malignancies. Mutations in the WAS gene can lead to distinct syndrome variations which largely, although not exclusively, depend upon the mutation. Premature termination and deletions abrogate Wiskott-Aldrich syndrome protein (WASp) expression and lead to severe disease (WAS). Missense mutations usually result in reduced protein expression and the phenotypically milder X-linked thrombocytopenia (XLT) or attenuated WAS [1-3]. More recently however novel activating mutations have been described that give rise to X-linked neutropenia (XLN), a third syndrome defined by neutropenia with variable myelodysplasia [4-6]. WASP is key in transducing signals from the cell surface to the actin cytoskeleton, and 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.

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“…For biochemical experiments, tubulin was purified in large scale from lamb brain by ammonium sulfate fractionation, ion exchange chromatography and precipitation with magnesium (33,49). Purified tubulin was stored in liquid nitrogen and prepared for use as described (45).…”

Section: Methodsmentioning

confidence: 99%

Stathmin and Interfacial Microtubule Inhibitors Recognize a Naturally Curved Conformation of Tubulin Dimers

Barbier

Dorléans

Devred

et al. 2010

Journal of Biological Chemistry

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Tubulin is able to switch between a straight microtubule-like structure and a curved structure in complex with the stathminlike domain of the RB3 protein (T 2 RB3). GTP hydrolysis following microtubule assembly induces protofilament curvature and disassembly. The conformation of the labile tubulin heterodimers is unknown. One important question is whether free GDP-tubulin dimers are straightened by GTP binding or if GTP-tubulin is also curved and switches into a straight conformation upon assembly. We have obtained insight into the bending flexibility of tubulin by analyzing the interplay of tubulinstathmin association with the binding of several small molecule inhibitors to the colchicine domain at the tubulin intradimer interface, combining structural and biochemical approaches. The crystal structures of T 2 RB3 complexes with the chiral R and S isomers of ethyl-5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl-carbamate, show that their binding site overlaps with colchicine ring A and that both complexes have the same curvature as unliganded T 2 RB3. The binding of these ligands is incompatible with a straight tubulin structure in microtubules. Analytical ultracentrifugation and binding measurements show that tubulin-stathmin associations (T 2 RB3, T 2 Stath) and binding of ligands (R, S, TN-16, or the colchicine analogue MTC) are thermodynamically independent from one another, irrespective of tubulin being bound to GTP or GDP. The fact that the interfacial ligands bind equally well to tubulin dimers or stathmin complexes supports a bent conformation of the free tubulin dimers. It is tempting to speculate that stathmin evolved to recognize curved structures in unassembled and disassembling tubulin, thus regulating microtubule assembly.Microtubules are essential for eukaryotic chromosome segregation, cellular architecture and intracellular trafficking, among other processes. Understanding microtubule dynamics, regulation, and organization requires knowledge of the nucleotide-regulated assembly switch of tubulin. Microtubules are hollow cylinders made of protofilaments of ␣␤-tubulin dimers in head to tail association, forming a pseudohelical lattice (1). The functional assembly-disassembly cycle of a ␣␤-tubulin molecule includes activation by GTP binding at the ␤-subunit, polymerization into microtubules, GTP hydrolysis at the ␤-␣ interdimer interface and depolymerization of GDP-tubulin, followed by replacement by GTP. Vectorial polymerization and GTP hydrolysis combine with tubulin structural plasticity in microtubule dynamics (2). Depolymerizing microtubule ends show characteristic curled protofilaments, whereas relatively straight sheets form at growing ends (3, 4). GDP-tubulin does not assemble into microtubules, but forms double rings (5), which also form upon microtubule depolymerization (6) and correspond to curved microtubule protofilaments (7,8). The tendency of GDP-tubulin to curve is thought to strain the microtubule lattice, causing disassembly when the terminal cap of GTP-bound tubulin...

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Novel membrane cell projection defects in Wiskott-Aldrich syndrome B cells

Cited by 6 publications

References 28 publications

Wiskott‐Aldrich syndrome: a comprehensive review

Wiskott‐Aldrich syndrome: a comprehensive review

The Wiskott-Aldrich Syndrome: The Actin Cytoskeleton and Immune Cell Function

Stathmin and Interfacial Microtubule Inhibitors Recognize a Naturally Curved Conformation of Tubulin Dimers

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