Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA.
Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA.
Int J Mol Sci. 2023 Jul 28;24(15):12081. doi: 10.3390/ijms241512081.
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.
肥大细胞在从未发生过过敏反应的物种中已经存在了数百万年。因此，除了过敏反应之外，肥大细胞还可以通过分泌许多血管活性、促炎和神经敏化介质在体内平衡和炎症中发挥关键作用。分泌可以利用涉及细胞骨架的不同模式，但我们对调节分泌的分子机制的理解仍不透彻。Ezrin/Radixin/Moesin（ERM）蛋白家族参与将细胞表面起始的信号传递到肌动蛋白细胞骨架。然而，ERM 如何调节肥大细胞的分泌仍知之甚少。ERM 包含两个通过长α-螺旋区域连接的功能域，即 N 端 FERM（带 4.1 蛋白-ERM）结构域和 C 端 ERM 结合结构域（C-ERMAD）。FERM 结构域和 C-ERMAD 可以以头尾相连的方式相互结合，导致封闭/无活性构象。通常，C 端 Thr 的磷酸化与 ERM 的激活有关，包括巨噬细胞和血小板的分泌。以前已经表明，所谓的肥大细胞“稳定剂”二钠色甘酸钠（色甘酸钠）抑制大鼠肥大细胞分泌的能力与一种 78 kDa 蛋白的磷酸化密切相关，该蛋白随后被证明是 ERM 家族的 moesin。有趣的是，moesin 在抑制肥大细胞分泌过程中的磷酸化位于 N 端 Ser56/74 和 Thr66 残基上。这种磷酸化模式可以将 moesin 锁定在无活性状态，使其无法与可溶性 NSF 附着蛋白受体（SNAREs）和突触相关蛋白（SNAPs）结合，这些蛋白对于胞吐作用至关重要。使用共聚焦显微镜成像，我们发现 moesin 在抑制分泌时与肌动蛋白共定位，并聚集在分泌颗粒周围。总之，moesin 的磷酸化模式和定位可能在肥大细胞分泌的调节中很重要，并且可能成为开发有效抑制肥大细胞释放过敏和炎症介质的抑制剂的靶点。
