Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes

Abstract

X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott

Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation

“…Study of animal models deficient for WASP expression or expressing WASP cannot explain mycolactone cytotoxicity in anchorage-independent cells, such as T lymphocytes (11). Activating mutations in WASP have been shown to increase apoptosis in T cells by promoting genomic instability, providing a possible mechanism for the mild cytopathic activity of mycolactone in this cell population (36). With regard to its immunomodulatory properties, recent studies indicating that WASP is an epigenetic regulator of Th1 (Invitrogen) and 2 mM l-glutamine (Sigma-Aldrich).…”

Disruption of hSWI/SNF complexes in T cells by WAS mutations distinguishes X-linked thrombocytopenia from Wiskott-Aldrich syndrome

“…58 Because H2A.Z is also important in DNA repair, determining whether and how WASp effects on H2A-to-H2A.Z exchange at other genomic loci affects this process will begin to clarify why certain WAS mutations associate with genomic instability in lymphocytes. 59 Given the importance of chromatin remodeling in biology, including in cancer development, 48,49,[60][61][62][63] we predict that the WASp:SWI/SNF alliance may affect multiple other-cell biological processes including tumor suppression, the disruption of which may further influence the phenotypic variations in WAS. Notwithstanding, the implications of our studies should be limited to the T H 1 development, because we have not studied megakaryocytes, the major cell type responsible for the early findings of thrombocytopenia (XLT) in WAS.…”

Excess F-actin mechanically impedes mitosis leading to cytokinesis failure in X-linked neutropenia by exceeding Aurora B kinase error correction capacity

“…2,4,6 The link between the constitutively active mutant of the WASp (CA-WASp) expression and chromosomal instability is supported by the recent demonstration of chromosomal changes in a murine model of the disease. 7 In cells, CA-WASp leads to a dramatic increase in F-actin that permeates the entire cytoplasm and surrounds chromosomes during mitosis resulting in an increase in the time necessary to complete mitosis and subsequent generation of micronucleated and binucleated cells. 2 As a dynamic mechanical process, cell division is sensitive to the mechanical properties of the cell, with alterations beyond normal tolerances leading to errors in spindle positioning and assembly, chromosome segregation, and cytokinesis.…”