Coronin 1A depletion restores the nuclear stability and viability of Aip1/Wdr1-deficient neutrophils

Bowes, Charnese; Redd, Michael J.; Yousfi, Malika; Tauzin, Muriel; Murayama, Emi; Herbomel, Philippe

doi:10.1083/jcb.201901024

Cited by 12 publications

(14 citation statements)

References 64 publications

(106 reference statements)

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“…Surprisingly, depleting Wdr1 in A20 B cells also resulted in cofilin activation, as indicated by a substantial reduction in the amount of inactive S3-phosphorylated cofilin ( Figure 1E ). Similar observations have been reported in developing zebrafish neutrophils, where Wdr1 depletion results in constitutive activation of cofilin but an accumulation of actin filaments that is likely due to reduced actin severing by cofilin when Wdr1 is absent (Bowes et al, 2019 ). Indeed, we show below that depleting Wdr1 largely phenocopied the effects of depleting cofilin, presumably because Wdr1 optimizes cofilin-mediated filament severing.…”

Section: Resultssupporting

confidence: 83%

“…In the absence of Wdr1, the saturation of actin filaments with cofilin would stabilize the filaments and prevent actin network remodeling. Indeed, depleting Wdr1 in the neutrophils of developing zebrafish, which also causes cofilin dephosphorylation, results in an accumulation of actin filaments (Bowes et al, 2019 ). A reduction in cofilin-mediated actin network disassembly may also limit the recycling of Arp2/3 complexes and actin monomers that supports new actin polymerization.…”

Section: Discussionmentioning

confidence: 99%

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The Wdr1-LIMK-Cofilin Axis Controls B Cell Antigen Receptor-Induced Actin Remodeling and Signaling at the Immune Synapse

Bolger-Munro

Choi

Cheung

et al. 2021

Front. Cell Dev. Biol.

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When B cells encounter membrane-bound antigens, the formation and coalescence of B cell antigen receptor (BCR) microclusters amplifies BCR signaling. The ability of B cells to probe the surface of antigen-presenting cells (APCs) and respond to APC-bound antigens requires remodeling of the actin cytoskeleton. Initial BCR signaling stimulates actin-related protein (Arp) 2/3 complex-dependent actin polymerization, which drives B cell spreading as well as the centripetal movement and coalescence of BCR microclusters at the B cell-APC synapse. Sustained actin polymerization depends on concomitant actin filament depolymerization, which enables the recycling of actin monomers and Arp2/3 complexes. Cofilin-mediated severing of actin filaments is a rate-limiting step in the morphological changes that occur during immune synapse formation. Hence, regulators of cofilin activity such as WD repeat-containing protein 1 (Wdr1), LIM domain kinase (LIMK), and coactosin-like 1 (Cotl1) may also be essential for actin-dependent processes in B cells. Wdr1 enhances cofilin-mediated actin disassembly. Conversely, Cotl1 competes with cofilin for binding to actin and LIMK phosphorylates cofilin and prevents it from binding to actin filaments. We now show that Wdr1 and LIMK have distinct roles in BCR-induced assembly of the peripheral actin structures that drive B cell spreading, and that cofilin, Wdr1, and LIMK all contribute to the actin-dependent amplification of BCR signaling at the immune synapse. Depleting Cotl1 had no effect on these processes. Thus, the Wdr1-LIMK-cofilin axis is critical for BCR-induced actin remodeling and for B cell responses to APC-bound antigens.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

The Wdr1-LIMK-Cofilin Axis Controls B Cell Antigen Receptor-Induced Actin Remodeling and Signaling at the Immune Synapse

Bolger-Munro

Choi

Cheung

et al. 2021

Front. Cell Dev. Biol.

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“…Wdr1-deficient neutrophils from zebrafish embryos have increased death rates accompanied by nuclear disorganization (Bowes et al, 2019). These cells have cytoplasmic clusters of Factin, and interestingly, cofilin is found unphosphorylated and bound to F-actin in these cells, which corroborates the functional interdependence of WDR1 and cofilin.…”

Section: Coroninsupporting

confidence: 56%

Emerging functions of cytoskeletal proteins in immune diseases

Tur-Gracia

Martı́nez-Quiles

2021

Journal of Cell Science

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Immune cells are especially dependent on the proper functioning of the actin cytoskeleton, and both innate and adaptive responses rely on it. Leukocytes need to adhere not only to substrates but also to cells in order to form synapses that pass on instructions or kill infected cells. Neutrophils literally squeeze their cell body during blood extravasation and efficiently migrate to the inflammatory focus. Moreover, the development of immune cells requires the remodeling of their cytoskeleton as it depends on, among other processes, adhesive contacts and migration. In recent years, the number of reports describing cytoskeletal defects that compromise the immune system has increased immensely. Furthermore, a new emerging paradigm points toward a role for the cellular actin content as an essential component of the so-called homeostasis-altering molecular processes that induce the activation of innate immune signaling pathways. Here, we review the role of critical actin-cytoskeleton-remodeling proteins, including the Arp2/3 complex, cofilin, coronin and WD40-repeat containing protein 1 (WDR1), in immune pathophysiology, with a special focus on autoimmune and autoinflammatory traits.

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“…17a, b). To further examine the role of Wdr1 in DMF-induced neutrophil apoptosis, we took advantage of fish carrying the Carmin allele, encoding a defunct Wdr1 protein 44 .…”

Section: Resultsmentioning

confidence: 99%

Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera

et al. 2021

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Despite the emerging importance of reactive electrophilic drugs, deconvolution of their principal targets remains difficult. The lack of genetic tractability/interventions and reliance on secondary validation using other non-specific compounds frequently complicate the earmarking of individual binders as functionally- or phenotypically-sufficient pathway regulators. Using a redox-targeting approach to interrogate how on-target binding of pleiotropic electrophiles translates to a phenotypic output in vivo, we here systematically track the molecular components attributable to innate immune cell toxicity of the electrophilic-drug dimethyl fumarate (Tecfidera®). In a process largely independent of canonical Keap1/Nrf2-signaling, Keap1-specific modification triggers mitochondrial-targeted neutrophil/macrophage apoptosis. On-target Keap1–ligand-engagement is accompanied by dissociation of Wdr1 from Keap1 and subsequent coordination with cofilin, intercepting Bax. This phagocytic-specific cell-killing program is recapitulated by whole-animal administration of dimethyl fumarate, where individual depletions of the players identified above robustly suppress apoptosis.

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Coronin 1A depletion restores the nuclear stability and viability of Aip1/Wdr1-deficient neutrophils

Cited by 12 publications

References 64 publications

The Wdr1-LIMK-Cofilin Axis Controls B Cell Antigen Receptor-Induced Actin Remodeling and Signaling at the Immune Synapse

The Wdr1-LIMK-Cofilin Axis Controls B Cell Antigen Receptor-Induced Actin Remodeling and Signaling at the Immune Synapse

Emerging functions of cytoskeletal proteins in immune diseases

Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera

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