Wiskott-Aldrich Syndrome Protein: Roles in Signal Transduction in T Cells

Abstract

Signal transduction regulates the proper function of T cells in an immune response. Upon binding to its specific ligand associated with major histocompatibility complex (MHC) molecules on an antigen presenting cell, the T cell receptor (TCR) initiates intracellular signaling that leads to extensive actin polymerization. Wiskott-Aldrich syndrome protein (WASp) is one of the actin nucleation factors that is recruited to TCR microclusters, where it is activated and regulates actin network formation. Here we highlight the research that has focused on WASp-deficient T cells from both human and mice in TCR-mediated signal transduction. We discuss the role of WASp in proximal TCR signaling as well as in the Ras/Rac-MAPK (mitogen-activated protein kinase), PKC (protein kinase C) and Ca²⁺-mediated signaling pathways.

Keywords: MAPK; PKC; T cell activation; T cell signaling; WASp; calcium.

FIGURE 1

Functional domains in WASp and WASp activation. (A) WASp contains various domains, which can bind proteins involved in TCR-mediated actin cytoskeleton remodeling and signal transduction. (B) WASp is in a closed auto-inhibited conformation in resting state due to its intracellular interaction between GBD and VCA domains. Upon TCR engagement, it mediates the binding of GTP-Cdc42 to the GBD domain, thereby releasing the VCA domain from GBD domain and changing the WASp structure into an opened conformation. In addition, WASp tyrosine 291 within GBD can be phosphorylated by the Src family kinases Fyn and Lck. Recruitment of GTP-Cdc42 to GBD and phosphorylation of WASp tyrosine 291 within GBD result in WASp activation. Subsequently, Arp2/3 and monomeric actin can bind the VCA domain, which induces a new actin branch. This figure was modified from Matalon et al. (2013). Wiskott-Aldrich syndrome protein–dynamic regulation of actin homeostasis: from activation through function and signal termination in T lymphocytes. Immunol. Rev. 256(1), 10–29; with a permission from John Wiley and Sons; license number 5065241058992.

FIGURE 2

The role of WASp in signal transduction in T cells. TCR ligation with pMHC triggers signal transduction within the cytoplasm of T cells. Once phosphorylated by ZAP-70, phospho-LAT recruits proteins to form the LAT/SLP-76 signalosome containing Nck and Vav. Vav activates the Rho GTPase Cdc42, which in turn interacts with WASp. This complex is recruited to the signalosome via Nck. In association with GTP-Cdc42, WASp is released from the auto-inhibited conformation and then initiates the ARP2/3-dependent F-actin polymerization. In Ras/Rac-MAPK pathway, WASp is essential for the translocation of phospho-Erk1/2 into the nucleus. Once in the nucleus, phospho-Erk1/2 phosphorylates Elk1, which then causes c-fos expression, a component of transcription factor AP-1. WASp was not required for the activation of Jnk, a kinase causing c-jun expression that is the second component of AP-1. In the PKC pathway, WASp contributes to PKCθ activation in response to low doses of antigen. Activated PKCθ is required for activation of transcription factor NF-κB and its nuclear translocation. For Ca²⁺-mediated signaling, WASp is indispensable for intracellular Ca²⁺ mobilization, which is essential for NFAT translocation to the nucleus. In the squared box, two alternative pathways of WASp recruitment to TCR are shown. Firstly, WASp is constitutively associated with Nck and Nck-WASp is recruited to the TCR upon TCR ligation. Secondly, preformed CrkL-WIP-WASp is recruited to ZAP-70 following T cell activation. We propose that these two recent identified pools of WASp play a role in controlling actin polymerization and may contribute to the nuclear translocation of phospho-Erk1/2, PKCθ-mediated NF-κB activation and Ca²⁺ influx.