STAT3 Couples with 14-3-3σ to Regulate BCR Signaling, B-cell Differentiation, and IgE Production.
The journal of allergy and clinical immunology/Journal of allergy and clinical immunology/The journal of allergy and clinical immunology(2021)
Abstract
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-cellintrinsic 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, 14-3-3 sigma, 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 14-3-3 sigma was associated with increased expression of the upstream mediator, microRNA146A. Inhibition of 14-3-3 sigma 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-14-3-3 sigma to regulate BCR signaling, peripheral B-cell differentiation, and IgE production.
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Key words
STAT3,HIES,B cells,BCR,14-3-3 sigma protein
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