ARPC1B binds WASP to control actin polymerization and curtail tonic signaling in B cells.

Immune cells exhibit low-level, constitutive signaling at rest (tonic signaling). Such tonic signals are required for fundamental processes, including the survival of B lymphocytes, but when elevated by genetic or environmental causes can lead to autoimmunity. Events that control ongoing signal transduction are therefore tightly regulated by submembrane cytoskeletal polymers like filamentous (F)-actin. The actin-binding proteins that underpin the process, however, are poorly described. By investigating patients with ARPC1B-deficiency, we report that ARPC1B-containing ARP2/3 complexes are stimulated by Wiskott Aldrich Syndrome protein (WASP) to nucleate the branched actin networks that control tonic signaling from the B cell receptor (BCR). Despite an upregulation of ARPC1A, ARPC1B-deficient cells were not capable of WASP-mediated nucleation by ARP2/3 and this caused the loss of WASP-dependent structures including podosomes in macrophages and lamellipodia in B cells. In the B cell compartment, ARPC1B-deficiency also led to weakening of the cortical F-actin cytoskeleton that normally curtails the diffusion of B cell receptors and ultimately resulted in increased tonic lipid signaling, oscillatory calcium release from the endoplasmic reticulum (ER), and phosphorylated Akt. These events contributed to skewing the threshold for B cell activation in response to microbial associated molecular patterns (MAMPs). Thus, ARPC1B is critical for ARP2/3 complexes to control steady-state signaling of immune cells.