Signal Transducer and Activator of Transcription 3 (STAT3) Variant p.K709N Causes Hyper-IgE Syndrome Likely by Impaired STAT3-Dimer Formation

IF 3.7 3区 医学 Q2 IMMUNOLOGY
Beate Hagl, Benedikt D. Spielberger, Betina Neumann, Simon J. Pelham, Dharmendra Pandey, Andreas Schlundt, Camille Barro, Anica Lechner, Christine Wolf, Elissa K. Deenick, Michael Sattler, Stuart G. Tangye, Simon Rothenfusser, Ellen D. Renner
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Abstract

STAT3-hyper-IgE syndrome (STAT3-HIES) is an inborn error of immunity caused by heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3). In this study, we evaluate the functional relevance of a previously undescribed heterozygous STAT3 variant in a patient with clinical findings of STAT3-HIES. Flow cytometry, quantitative real-time PCR, pull-down assays, native PAGE, DNA-binding ELISA, and 3D-structural data analysis were performed. Genetic analysis identified the heterozygous STAT3 variant NM_139276.2:c.2127G>C (NP_644805.1:p.(K709N); short: p.K709N) in a patient with a clinical and laboratory phenotype characteristic of STAT3-HIES, including early onset severe eczema, chronic lung disease, eosinophilia, and elevated serum IgE levels. While STAT3 p.K709N did not significantly affect STAT3 phosphorylation, STAT3 target gene expression was impaired in patient cells. Expression of STAT3 p.K709N and wild-type STAT3 in STAT3-deficient cells indicated a dominant-negative effect by the mutation. Analysis of 3D-structural data and modeling suggested a central role of the affected amino acid K709 in stabilizing a C-terminal loop in STAT3 essential for dimer formation. Consequently, p.K709N resulted in diminished STAT3 dimerization and reduced DNA binding in patient cells. Functional analyses verified STAT3 p.K709N to cause STAT3-HIES and suggest that STAT3 p.K709N impairs STAT3 dimer formation.

Abstract Image

信号换能器和转录激活子3 (STAT3)变异体p.K709N可能因STAT3二聚体形成受损而导致高ige综合征
STAT3-高ige综合征(STAT3- hies)是由转录信号转导因子和激活因子3 (STAT3)杂合显性负突变引起的先天性免疫错误。在这项研究中,我们评估了一名临床表现为STAT3- hies的患者中先前未描述的杂合STAT3变异的功能相关性。流式细胞术、实时荧光定量PCR、拉下实验、天然PAGE、dna结合ELISA和3d结构数据分析。遗传分析鉴定出STAT3杂合变异体NM_139276.2: C . 2127g >C (NP_644805.1:p.(K709N);简称:p.K709N),患者的临床和实验室表型特征为STAT3-HIES,包括早发性严重湿疹、慢性肺病、嗜酸性粒细胞增多和血清IgE水平升高。虽然STAT3 p.K709N对STAT3磷酸化没有显著影响,但STAT3靶基因在患者细胞中的表达受损。STAT3 p.K709N和野生型STAT3在STAT3缺陷细胞中的表达受突变的显性负作用。3d结构数据和建模分析表明,受影响的氨基酸K709在稳定二聚体形成所必需的STAT3 c端环中发挥了核心作用。因此,p.K709N导致患者细胞中STAT3二聚体的减少和DNA结合的减少。功能分析证实STAT3 p.K709N导致STAT3- hies,并提示STAT3 p.K709N损害STAT3二聚体的形成。
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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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