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

Abstract

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 actinbinding 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 WASPdependent structures including podosomes in macrophages and lamellipodia in B cells.In the B cell compartment, ARPC1B-deficiency also led to weakening of the cortical Factin 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 steadystate signaling of immune cells.

Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

“…In addition, such immune perturbation was associated to severe autoimmunity at the gastrointestinal level in our patients, with symptoms mimicking very early inflammatory bowel disease. Indeed, an altered B-cell tolerance resulting from defective BCR stimulation due to an altered actin polymerization has recently been described (14).…”

Actin related protein 2/3 complex subunit 1 up‐regulation in the hypothalamus prevents high‐fat diet induced obesity

“…ARPC1B deficiency leads to the cytoskeleton and functional defects in T lymphocytes, thus impairing immune synapse formation and causing immunodeficiency (Brigida et al, 2018; German et al, 2021). A recent study also demonstrated that ARPC1B was an important subunit for podosome formation in macrophages and lamellipodia formation in B cells, which was critical for controlling steady‐state signalling of immune cells (Leung et al, 2021). In addition, previous studies have primarily highlighted a prominent role of ARPC1B in the auto‐inflammation diseases (Kahr et al, 2017; Volpi et al, 2019).…”

Comparative proteomics analysis of human stem cells from dental gingival and periodontal ligament

“…ARPC1B was identified as a conserved core subcutaneous AT aging-related gene. ARPC1B deficiency results in a weakened cortical phosphorylated Akt [33,34]. PDAP1 encodes an RNA-binding protein that significantly contributes to the regulation of T cell proliferation.…”

“…ARPC1B was identified as a conserved core subcutaneous AT aging‐related gene. ARPC1B deficiency results in a weakened cortical F‐actin cytoskeleton, ultimately leading to tonic lipid signaling, oscillatory calcium release from the endoplasmic reticulum, and increased phosphorylated Akt [33, 34]. PDAP1 encodes an RNA‐binding protein that significantly contributes to the regulation of T cell proliferation.…”