Actinin‐4 controls survival signaling in B cells by limiting the lateral mobility of B‐cell antigen receptors

Abstract The structure and dynamics of F‐actin networks in the cortical area of B cells control the signal efficiency of B‐cell antigen receptors (BCRs). Although antigen‐induced signaling has been studied extensively, the role of cortical F‐actin in antigen‐independent tonic BCR signaling is less well understood. Because these signals are essential for the survival of B cells and are consequently exploited by several B‐cell lymphomas, we assessed how the cortical F‐actin structure influences tonic BCR signal transduction. We employed genetic variants of a primary cell‐like B‐cell line that can be rendered quiescent to show that cross‐linking of actin filaments by α‐actinin‐4 (ACTN4), but not ACTN1, is required to preserve the dense architecture of F‐actin in the cortical area of B cells. The reduced cortical F‐actin density in the absence of ACTN4 resulted in increased lateral BCR diffusion. Surprisingly, this was associated with reduced tonic activation of BCR‐proximal effector proteins, extracellular signal‐regulated kinase, and pro‐survival pathways. Accordingly, ACTN4‐deficient B‐cell lines and primary human B cells exhibit augmented apoptosis. Hence, our findings reveal that cortical F‐actin architecture regulates antigen‐independent tonic BCR survival signals in human B cells.