The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation

Abstract

The actin cytoskeleton is a dynamic cellular network known for its function in cell morphology and motility. Recent studies using high resolution and real time imaging techniques have revealed that actin plays a critical role in signal transduction, primarily by modulating the dynamics and organization of membrane-associated receptors and signaling molecules. This review summarizes what we have learned so far about a regulatory niche of the actin cytoskeleton in the signal transduction of the B cell receptor (BCR). The activation of the BCR is initiated and regulated by a close coordination between the dynamics of surface BCRs and the cortical actin network. The actin cytoskeleton is involved in regulating the signaling threshold of the BCR to antigenic stimulation, the kinetics and amplification of BCR signaling activities, and the timing and kinetics of signaling downregulation. Actin exerts its regulatory function by controlling the kinetics, magnitude, subcellular location, and nature of BCR clustering and BCR signaling complex formation at every stage of signaling. The cortical actin network is remodeled by initial detachment from the plasma membrane, disassembly and subsequent reassembly into new actin structures in response to antigenic stimulation. Signaling responsive actin regulators translate BCR stimulatory and inhibitory signals into a series of actin remodeling events, which enhance signaling activation and down-regulation by modulating the lateral mobility and spatial organization of surface BCR. The mechanistic understanding of actinmediated signaling regulation in B cells will help us explore B cell-specific manipulations of the actin cytoskeleton as treatments for B cell-mediated autoimmunity and B cell cancer. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters.

Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

“…Actin remodeling is associated with BCR signaling and requires Vav, PLCγ2, and Btk, which activate the Rho family GTPases Rac and Cdc42 that bind WASp (38,39). The absence of functional WASp may therefore interfere with actin remodeling and result in increased BCR function.…”

“…WASp is a regulator of actin dynamics and may therefore affect the signaling and trafficking of BCRs and TLRs (38,39). Actin remodeling is associated with BCR signaling and requires Vav, PLCγ2, and Btk, which activate the Rho family GTPases Rac and Cdc42 that bind WASp (38,39).…”

The Rap1–cofilin-1 pathway coordinates actin reorganization and MTOC polarization at the B cell immune synapse

“…This increases BCR mobility (Freeman et al, 2015;Treanor et al, 2010), allowing antigen-bound BCRs to form microclusters that recruit signaling enzymes Tolar et al, 2009;Treanor et al, 2009). Concomitant actin polymerization at the cell periphery allows the B cell to spread across the antigen-bearing surface, encounter more antigens, and form additional BCR microclusters (Fleire et al, 2006;Song et al, 2013). Subsequent contraction of the B cell membrane (Fleire et al, 2006) is accompanied by microtubule-dependent gathering of BCR microclusters into a central supramolecular activation cluster (cSMAC) (Schnyder et al, 2011) that is characteristic of an immune synapse (IS) (Dustin et al, 2010).…”

“…At the IS, B cells extract BCRbound antigens from APCs (Batista et al, 2001). These antigens are internalized and delivered to lysosomes and major histocompatibility complex (MHC) II-containing vesicles via actin-and microtubuledependent processes (Song et al, 2013;Yuseff et al, 2013). Resulting peptide-MHC-II complexes are presented to T cells, which provide additional signals for B cell activation.…”

“…These APCs capture antigens and display them on their surface in an intact form that is recognized by the B cell receptor (BCR) Cyster, 2010;Heesters et al, 2013). For membraneassociated antigens, BCR-induced reorganization of the actin and microtubule cytoskeletons is critical for the two functions of the BCR, signal transduction and antigen internalization Song et al, 2013;Yuseff et al, 2013). Initial BCR signaling at the B-cell-APC interface promotes disassembly of the submembrane actin network and uncouples the actin meshwork from the plasma membrane (Freeman et al, 2011;Treanor et al, 2011Treanor et al, , 2010.…”