Receptor dynamics regulates actin polymerization state through phosphorylation of cofilin in mast cells

Suzuki, Ruriko; Inoh, Yoshikazu; Yokawa, Satoru; Furuno, Tadahide; Hirashima, Naohide

doi:10.1016/j.bbrc.2020.11.012

Cited by 9 publications

(4 citation statements)

References 21 publications

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“…For example, antigen binding to B-cell receptor (BCR) causes depolymerization of cortical actin and increased mobility of BCR due to the transient activation of cofilin (an actin depolymerization factor); this results in efficient downstream signal transduction [57][58][59]. Similarly, cofilin is transiently activated after IgE/Ag stimulation in mast cells [60], and the balance between polymerization and depolymerization of actin influences the level of FcεRI aggregation [61]. The mobility and size of the FcεRI cluster are related to the initiation and propagation of downstream signaling [62,63].…”

Section: Discussionmentioning

confidence: 99%

Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

Kondo,

Suzuki,

Matsumura

et al. 2023

Eur J Immunol

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In the present study, we found that methiothepin (a non‐selective 5‐hydroxytryptamine (5‐HT) receptor antagonist) inhibited antigen‐induced degranulation in rat basophilic leukemia cells and mouse bone marrow‐derived mast cells. Although antigen stimulation induces release of histamine and serotonin (5‐HT) by exocytosis and mast cells express several types of 5‐HT receptor, the detailed role of these receptors remains unclear. Here, pretreatment of cells with methiothepin attenuated increased intracellular Ca2+ concentration, phosphorylated critical upstream signaling components: SFKs, Syk, and PLCγ1, and suppressed TNF‐α secretion via inhibition of Akt and ERK phosphorylation. Furthermore, it inhibited PMA/ionomycin‐induced degranulation; this finding suggested that methiothepin affected downstream signaling. IκB kinase β (IKKβ) phosphorylates synaptosomal associated protein 23 (SNAP23), which regulates the fusion events of the secretory granule/plasma membrane after mast cell activation, resulting in degranulation. We showed that methiothepin blocked PMA/ionomycin‐induced phosphorylation of SNAP23 by inhibiting its interaction with IKKβ. Together with the results of selective 5‐HT antagonists, it is suggested that methiothepin inhibits mast cell degranulation by downregulating upstream signaling pathways and exocytotic fusion machinery through mainly 5‐HT1A receptor. Our findings provide that 5‐HT antagonists may be used to relieve allergic reactions.This article is protected by copyright. All rights reserved

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Section: Discussionmentioning

confidence: 99%

Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

Kondo,

Suzuki,

Matsumura

et al. 2023

Eur J Immunol

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“…Like other mammalian cells, a cortical actin network supports the plasma membrane of mast cells. In general, half of the actin is found as globular-actin (monomeric, G-actin), and the rest is polymerized into actin's filamentous (filaments, F-actin), which form mainly the cortical cytoskeleton of actin (Suzuki et al, 2021). Mast cells are specialized in secretion, and cortical actin plays an essential role during degranulation.…”

Section: Discussionmentioning

confidence: 99%

Dehydroleucodine and xanthatin, two natural anti‐inflammatory lactones, inhibit mast cell degranulation by affecting the actin cytoskeleton

Wetten,

Arismendi Sosa,

Mariani

et al. 2023

Cytoskeleton

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Actin remodeling is a critical regulator of mast cell secretion. In previous work, we have shown that dehydroleucodine and xanthatin, two natural α,β‐unsaturated lactones, exhibit anti‐inflammatory and mast cell stabilizing properties. Based on this background, this study aimed to determine whether the mast cell stabilizing action of these lactones is associated with changes in the actin cytoskeleton. Rat peritoneal mast cells were preincubated in the presence of dehydroleucodine or xanthatin before incubation with compound 48/80. Comparative studies with sodium cromoglycate and latrunculin B were also made. After treatments, different assays were performed on mast cell samples: β‐hexosaminidase release, cell viability studies, quantification of mast cells and their state of degranulation by light microscopy, transmission electron microscopy, and actin staining for microscopy observation. Results showed that dehydroleucodine and xanthatin inhibited mast cell degranulation, evidenced by the inhibition of β‐hexosaminidase release and decreased degranulated mast cell percentage. At the same time, both lactones altered the F‐actin cytoskeleton in mast cells resulting, similarly to Latrunculin B, in a higher concentration of nuclear F‐actin when activated by compound 48/80. For the first time, this study describes the biological properties of dehydroleucodine and xanthatin concerning to the rearrangement of actin filaments during stimulated exocytosis in mast cells. These data have important implications for developing new anti‐inflammatory and mast cell stabilizing drugs and for designing new small molecules that may interact with the actin cytoskeleton.

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“…Mast cells, like any other secretory cell, require the actin cytoskeleton [147] that is necessary for signal transduction and movement of secretory granules or vesicles destined for secretion to the cell surface. For instance, the aggregation of IgE bound to FcεRI by a multivalent antigen stimulates mast cell secretion and rapidly depolymerizes actin filaments, with the actin-severing protein cofilin being dephosphorylated several minutes after stimulation [148]. In contrast, the disaggregation of IgE terminates degranulation mediated by dephosphorylation of Syk associated with a decrease in intracellular Ca 2+ concentration and rapid recovery of actin polymerization.…”

Section: Moesin In Mast Cellsmentioning

confidence: 99%

Potential Role of Moesin in Regulating Mast Cell Secretion

Kempuraj

2023

IJMS

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Mast cells have existed for millions of years in species that never suffer from allergic reactions. Hence, in addition to allergies, mast cells can play a critical role in homeostasis and inflammation via secretion of numerous vasoactive, pro-inflammatory and neuro-sensitizing mediators. Secretion may utilize different modes that involve the cytoskeleton, but our understanding of the molecular mechanisms regulating secretion is still not well understood. The Ezrin/Radixin/Moesin (ERM) family of proteins is involved in linking cell surface-initiated signaling to the actin cytoskeleton. However, how ERMs may regulate secretion from mast cells is still poorly understood. ERMs contain two functional domains connected through a long α-helix region, the N-terminal FERM (band 4.1 protein-ERM) domain and the C-terminal ERM association domain (C-ERMAD). The FERM domain and the C-ERMAD can bind to each other in a head-to-tail manner, leading to a closed/inactive conformation. Typically, phosphorylation on the C-terminus Thr has been associated with the activation of ERMs, including secretion from macrophages and platelets. It has previously been shown that the ability of the so-called mast cell “stabilizer” disodium cromoglycate (cromolyn) to inhibit secretion from rat mast cells closely paralleled the phosphorylation of a 78 kDa protein, which was subsequently shown to be moesin, a member of ERMs. Interestingly, the phosphorylation of moesin during the inhibition of mast cell secretion was on the N-terminal Ser56/74 and Thr66 residues. This phosphorylation pattern could lock moesin in its inactive state and render it inaccessible to binding to the Soluble NSF attachment protein receptors (SNAREs) and synaptosomal-associated proteins (SNAPs) critical for exocytosis. Using confocal microscopic imaging, we showed moesin was found to colocalize with actin and cluster around secretory granules during inhibition of secretion. In conclusion, the phosphorylation pattern and localization of moesin may be important in the regulation of mast cell secretion and could be targeted for the development of effective inhibitors of secretion of allergic and inflammatory mediators from mast cells.

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Receptor dynamics regulates actin polymerization state through phosphorylation of cofilin in mast cells

Cited by 9 publications

References 21 publications

Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

Methiothepin downregulates SNAP‐23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow‐derived mast cells

Dehydroleucodine and xanthatin, two natural anti‐inflammatory lactones, inhibit mast cell degranulation by affecting the actin cytoskeleton

Potential Role of Moesin in Regulating Mast Cell Secretion

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