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 they are elevated by genetic or environmental causes, they can lead to autoimmunity. Events that control ongoing signal transduction are, therefore, tightly regulated by submembrane cytoskeletal polymers like 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 BCRs 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.
Highlights
ARPC1B-deficiency is a recently described, rare genetic disorder that causes a Wiskott-Aldrich Syndrome (WAS)-like disease in children [1,2,3]
By immunoblotting lysates made from the lymphoblastoid cell lines (LCL), we confirmed the loss of ARPC1B in the patient-derived B cells and found that this was concomitant with an upregulation in the expression of the ARPC1A (Fig 1B)
Despite the upregulation of ARPC1A, the total F-actin density of the cells determined by measuring the mean fluorescence intensity of Alexa Fluor 488-phalloidin was decreased 2- to 3-fold in those derived from patients versus healthy cells (Fig 1C, S Fig 1)
Summary
ARPC1B-deficiency is a recently described, rare genetic disorder that causes a Wiskott-Aldrich Syndrome (WAS)-like disease in children [1,2,3]. It follows an autosomal recessive inheritance pattern and is clinically marked by leukocytoclastic vasculitis, thrombocytopenia, immune defects, eczema, otitis media, and bloody eosinophilic colitis. Isoforms of the ARP2/3 complex subunits, as well as the NPFs that stimulate ARP2/3, show recent evolutionary divergence and tissue specific expression patterns. The two ARPC1 isoforms in humans share 67% sequence identity and while ARPC1A has a largely ubiquitous expression pattern, ARPC1B is uniquely and highly expressed in immune cells [11]. In the organisms that express one ARPC1 isoform, the subunit can be essential for life [12], an understanding for the emergence of its isoforms in humans remains unknown
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