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

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 alpha-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. ACTN4 and the cortical F-actin network control tonic BCR survival signals. In resting B cells, the cortical F-actin cytoskeleton confines the lateral mobility of BCR complexes, leading to ITAM phosphorylation within CD79A/B and subsequent SYK activation to initiate survival signals. In the absence of ACTN4, the cortical F-actin network cannot confine the lateral BCR mobility and possibly renders the transient formation of BCR-dimers less likely, which reduces the efficiency of ITAM phosphorylation, SYK activation, and subsequent survival signals. Created with BioRender.com. image