Wiskott–Aldrich syndrome protein – dynamic regulation of actin homeostasis: from activation through function and signal termination in T lymphocytes

Abstract

The actin cytoskeleton network forms a key link between T-cell antigen receptor (TCR) stimulation and T-cell effector functions, providing a structural basis for T-cell morphological changes and signal transduction. Accumulating evidence positions the Wiskott-Aldrich syndrome protein (WASp), a scaffolding protein that promotes actin polymerization, at the center of actin cytoskeleton-dependent T-cell function. During the past decade, we and others have utilized multidisciplinary technologies, including live-cell imaging, biochemical, and biophysical analyses, to gain insight into the mechanisms by which WASp and other cytoskeletal proteins control actin homeostasis. Following TCR engagement, WASp is rapidly activated and recruited to TCR microclusters, as part of multiprotein complexes, where it promotes actin remodeling. Late in the activation process, WASp is internalized and eventually degraded. In this review, we describe the dynamic interactions of WASp with signaling proteins, which regulate its activation and recruitment to the TCR and to actin-rich sites. Finally, we present the molecular mechanism of WASp downregulation. Some of the signaling proteins that mediate WASp activation eventually lead to its degradation. Thus, we focus here on the regulation of WASp expression and function and the mechanisms whereby they control actin machinery and T-cell effector functions.

New insights into the role of the disordered WIP N‐terminal domain revealed by NMR structural characterization

“…A possible hypothesis is that the 'contracted' helical region tethering the two extended segments limits their maximal separation in space and lowers the effective radius of gyration for the entire fragment. The weighted-average r g for the RDC-constrained ensemble was [29][30] A. A comparison of this estimate to literature values [72] supports our conclusions.…”

Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters

“…In contrast, LAT-dependent SLP-76 clusters have a direct role in activating the Arp2/3 complex and actin polymerization. After TCR engagement, WASp and WAVE2 are rapidly recruited to the LAT signaling complex (14, 58), although they disassociate to form separate structures after longer stimulation times (14). The association of WASp, WAVE2, and SLP-76 with LAT may be important for coordinating the correct spatial context to initiate the actin polymerization necessary for dSMAC and pSMAC formation.…”

Next Generation Sequencing Reveals Skewing of the T and B Cell Receptor Repertoires in Patients with Wiskott–Aldrich Syndrome

“…Patients are also predisposed to autoimmunity and malignancy, resulting in poor clinical outcome overall (3, 4). The WAS gene encodes for the WAS protein (WASp) (5), which is expressed solely in hematopoietic cells, and is recruited to the inner cell membrane in response to activating signals, including engagement of the T and B cell antigen receptors (TCR and BCR) (6, 7). Upon activation, WASp recruits the Arp2/3 complex, triggering actin polymerization (8).…”