STAT3 与 14-3-3σ 结合来调节 BCR 信号转导、B 细胞分化和 IgE 产生。
STAT3 couples with 14-3-3σ to regulate BCR signaling, B-cell differentiation, and IgE production.
机构信息
Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorder, Children's Hospital of Chongqing Medical University, Chongqing, China; International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorder, Children's Hospital of Chongqing Medical University, Chongqing, China; International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Dermatology, Children's Hospital of Chongqing Medical University, Chongqing, China.
出版信息
J Allergy Clin Immunol. 2021 May;147(5):1907-1923.e6. doi: 10.1016/j.jaci.2020.09.033. Epub 2020 Oct 9.
BACKGROUND
STAT3 or dedicator of cytokinesis protein 8 (Dock8) loss-of-function (LOF) mutations cause hyper-IgE syndrome. The role of abnormal T-cell function has been extensively investigated; however, the contribution of B-cell-intrinsic dysfunction to elevated IgE levels is unclear.
OBJECTIVE
We sought to determine the underlying molecular mechanism of how STAT3 regulates B-cell receptor (BCR) signaling, B-cell differentiation, and IgE production.
METHODS
We used samples from patients with STAT3 LOF mutation and samples from the STAT3 B-cell-specific knockout (KO) mice Mb1Stat3 mice (B-STAT3 KO) to investigate the mechanism of hyper-IgE syndrome.
RESULTS
We found that the peripheral B-cell homeostasis in B-STAT3 KO mice mimicked the phenotype of patients with STAT3 LOF mutation, having decreased levels of follicular and germinal center B cells but increased levels of marginal zone and IgE B cells. Furthermore, B-STAT3 KO B cells had reduced BCR signaling following antigenic stimulation owing to reduced BCR clustering and decreased accumulation of Wiskott-Aldrich syndrome protein and F-actin. Excitingly, a central hub protein, 14-3-3σ, which is essential for the increase in IgE production, was enhanced in the B cells of B-STAT3 KO mice and patients with STAT3 LOF mutation. The increase of 14-3-3σ was associated with increased expression of the upstream mediator, microRNA146A. Inhibition of 14-3-3σ with R18 peptide in B-STAT3 KO mice rescued the BCR signaling, follicular, germinal center, and IgE B-cell differentiation to the degree seen in wild-type mice.
CONCLUSIONS
Altogether, our study has established a novel regulatory pathway of STAT3-miRNA146A-14-3-3σ to regulate BCR signaling, peripheral B-cell differentiation, and IgE production.
背景
信号转导和转录激活因子 3（STAT3）或胞质分裂蛋白 8（Dock8）功能丧失（LOF）突变导致高免疫球蛋白 E 综合征。异常 T 细胞功能的作用已被广泛研究；然而，B 细胞内在功能障碍对升高的 IgE 水平的贡献尚不清楚。
目的
我们旨在确定 STAT3 如何调节 B 细胞受体（BCR）信号、B 细胞分化和 IgE 产生的基本分子机制。
方法
我们使用来自 STAT3 LOF 突变患者的样本和 STAT3 B 细胞特异性敲除（KO）小鼠 Mb1Stat3 小鼠（B-STAT3 KO）的样本来研究高免疫球蛋白 E 综合征的机制。
结果
我们发现，B-STAT3 KO 小鼠的外周 B 细胞稳态模拟了 STAT3 LOF 突变患者的表型，滤泡和生发中心 B 细胞水平降低，但边缘区和 IgE B 细胞水平升高。此外，由于 BCR 聚类减少和 Wiskott-Aldrich 综合征蛋白和 F- 肌动蛋白的积累减少，B-STAT3 KO B 细胞在抗原刺激后 BCR 信号转导减少。令人兴奋的是，一种中枢枢纽蛋白 14-3-3σ，它是增加 IgE 产生所必需的，在 B-STAT3 KO 小鼠和 STAT3 LOF 突变患者的 B 细胞中增强。14-3-3σ 的增加与上游介质 microRNA146A 的表达增加有关。在 B-STAT3 KO 小鼠中用 R18 肽抑制 14-3-3σ 可挽救 BCR 信号转导、滤泡、生发中心和 IgE B 细胞分化，程度与野生型小鼠相似。
结论
总之，我们的研究建立了 STAT3-miRNA146A-14-3-3σ 的新调节途径，以调节 BCR 信号转导、外周 B 细胞分化和 IgE 产生。
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