The Lack of WIP Binding to Actin Results in Impaired B Cell Migration and Altered Humoral Immune Responses

Abstract

Summary: Wiskott-Aldrich syndrome protein (WASp) is a main cytoskeletal regulator in B cells. WASp-interacting protein (WIP) binds to and stabilizes WASp but also interacts with actin. Using mice with a mutated actin binding domain of WIP (WIPΔABD), we here investigated the role of WIP binding to actin during B cell activation. We found an altered differentiation of WIPΔABD B cells and diminished antibody affinity maturation after immunization. Mechanistically, WIPΔABD B cells showed impaired B cell receptor (BCR)-induced PI3K signaling and actin reorganization, likely caused by diminished CD81 expression and altered CD19 dynamics on the B cell surface. WIPΔABD B cells displayed reduced in vivo motility, concomitantly with impaired chemotaxis and defective F-actin polarization, HS1 phosphorylation, and polarization of HS1 to F-actin-rich structures after CXCL12 stimulation in vitro. We thus concluded that WIP binding to actin, independent of its binding to WASp, is critical for actin cytoskeleton plasticity in B cells. : The absence of WIP in mouse and human triggers immunodeficiency mimicking Wiskott-Aldrich syndrome. Keppler et al. report that binding of WIP to actin shapes actin cytoskeleton plasticity in B cells; is sufficient to modulate signaling, chemotaxis, and in vivo migration; and hence influences humoral immune responses. Keywords: B lymphocytes, chemotaxis, actin cytoskeleton, CXCR4, HS1, Wiskott-Aldrich syndrome, PI3K signaling