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肌动蛋白调节蛋白 Coronin1a 和 Coronin1b 对肥大细胞脱颗粒与细胞因子分泌的差异调节。

Differential regulation of mast cell degranulation versus cytokine secretion by the actin regulatory proteins Coronin1a and Coronin1b.

机构信息

Department of Immunology and Cell Biology, Research Center Borstel, 23845 Borstel, Germany.

出版信息

J Exp Med. 2011 Aug 29;208(9):1777-87. doi: 10.1084/jem.20101757. Epub 2011 Aug 15.

DOI:10.1084/jem.20101757
PMID:21844203
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3171099/
Abstract

Mast cell (MC) activation via aggregation of the high affinity IgE receptor (FcεRI) causes degranulation and release of proinflammatory mediators in a process that involves the reorganization of the actin cytoskeleton. However, the regulatory pathways and the molecular links between cytoskeletal changes and MC function are incompletely understood. In this study, we provide genetic evidence for a critical role of the actin-regulatory proteins Coronin1a (Coro1a) and Coro1b on exocytic pathways in MCs: Coro1a(-/-) bone marrow-derived MCs exhibit increased FcεRI-mediated degranulation of secretory lysosomes but significantly reduced secretion of cytokines. Hyperdegranulation of Coro1a(-/-) MCs is further augmented by the additional loss of Coro1b. In vivo, Coro1a(-/-)Coro1b(-/-) mice displayed enhanced passive cutaneous anaphylaxis. Functional reconstitution assays revealed that the inhibitory effect of Coro1a on MC degranulation strictly correlates with cortical localization of Coro1a, requires its filamentous actin-binding activity, and is regulated by phosphorylation of Ser2 of Coro1a. Thus, coronin proteins, and in turn the actin cytoskeleton, exhibit a functional dichotomy as differential regulators of degranulation versus cytokine secretion in MC biology.

摘要

肥大细胞（MC）通过高亲和力 IgE 受体（FcεRI）的聚集而被激活，导致脱颗粒和促炎介质的释放，这一过程涉及到肌动蛋白细胞骨架的重排。然而，细胞骨架变化与 MC 功能之间的调节途径和分子联系还不完全清楚。在这项研究中，我们提供了遗传证据，证明肌动蛋白调节蛋白 Coronin1a（Coro1a）和 Coro1b 在 MC 中的胞吐途径中起着关键作用：Coro1a（-/-）骨髓衍生的 MC 表现出更高的 FcεRI 介导的分泌溶酶体脱颗粒作用，但细胞因子的分泌显著减少。Coro1a（-/-）MC 的脱颗粒作用进一步增强了 Coro1b 的缺失。在体内，Coro1a（-/-）Coro1b（-/-）小鼠表现出增强的被动皮肤过敏反应。功能重建实验表明，Coro1a 对 MC 脱颗粒的抑制作用与 Coro1a 的皮质定位严格相关，需要其丝状肌动蛋白结合活性，并受 Coro1a 的 Ser2 磷酸化调节。因此，冠状蛋白，进而肌动蛋白细胞骨架，在 MC 生物学中表现出功能上的二分法，作为脱颗粒与细胞因子分泌的差异调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/7f3cefee07d6/JEM_20101757_RGB_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/9881d9f07d69/JEM_20101757_RGB_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/17c48ecc6d41/JEM_20101757_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/2298c67bb03e/JEM_20101757_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/1bf1a6a61754/JEM_20101757_RGB_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/7f3cefee07d6/JEM_20101757_RGB_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/9881d9f07d69/JEM_20101757_RGB_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/17c48ecc6d41/JEM_20101757_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/2298c67bb03e/JEM_20101757_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/1bf1a6a61754/JEM_20101757_RGB_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e43/3171099/7f3cefee07d6/JEM_20101757_RGB_Fig5.jpg

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