STAT3 couples with 14-3-3σ to regulate BCR signaling, B-cell differentiation, and IgE production,Journal of Allergy and Clinical Immunology

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STAT3 couples with 14-3-3σ to regulate BCR signaling, B-cell differentiation, and IgE production
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-10-09 , DOI: 10.1016/j.jaci.2020.09.033
Zuochen Du ₁ , Anwei Chen ₂ , Lu Huang ₃ , Xin Dai ₄ , Qiuyue Chen ₄ , Di Yang ₃ , Liling Li ₃ , Heather Miller ₅ , Lisa Westerberg ₆ , Yuan Ding ₇ , Xuemei Tang ₈ , Masato Kubo ₉ , Liping Jiang ₃ , Xiaodong Zhao ₃ , Hua Wang ₁₀ , Chaohong Liu ₄

Affiliation

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.
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 Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Mont.
Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.
Laboratory for Cytokine Regulation, Center for Integrative Medical Science, RIKEN Yokohama Institute, Kanagawa, Japan.
Department of Dermatology, Children's Hospital of Chongqing Medical University, Chongqing, China.

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 Mb1^Cre Stat3^flox/flox 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.

中文翻译：

STAT3 与 14-3-3σ 偶联来调节 BCR 信号传导、B 细胞分化和 IgE 产生

背景

STAT3 或胞质分裂蛋白 8 (Dock8) 功能丧失 (LOF) 突变会导致高 IgE 综合征。 T 细胞功能异常的作用已得到广泛研究；然而，B 细胞内在功能障碍对 IgE 水平升高的影响尚不清楚。

客观的

我们试图确定 STAT3 如何调节 B 细胞受体 (BCR) 信号传导、B 细胞分化和 IgE 产生的潜在分子机制。

方法

我们使用 STAT3 LOF 突变患者的样本和 STAT3 B 细胞特异性敲除 (KO) 小鼠Mb1 ^Cre Stat3 ^flox/flox小鼠 (B-STAT3 KO) 的样本来研究高 IgE 综合征的机制。

结果

我们发现 B-STAT3 KO 小鼠的外周 B 细胞稳态与 STAT3 LOF 突变患者的表型相似，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，B-STAT3 KO B 细胞在抗原刺激后减少了 BCR 信号传导，这是由于 BCR 聚集减少以及 Wiskott-Aldrich 综合征蛋白和 F-肌动蛋白积累减少。令人兴奋的是，一种对于增加 IgE 产生至关重要的中枢蛋白 14-3-3σ 在 B-STAT3 KO 小鼠和 STAT3 LOF 突变患者的 B 细胞中得到增强。 14-3-3σ 的增加与上游介质 microRNA146A 表达的增加相关。在 B-STAT3 KO 小鼠中用 R18 肽抑制 14-3-3σ 可挽救 BCR 信号传导、滤泡、生发中心和 IgE ⁺ B 细胞分化，达到野生型小鼠中所见的程度。