The type 1 diabetes candidate genes PTPN2 and BACH2 regulate the IFN-α-induced crosstalk between JAK/STAT and MAPKs pathways in human beta cells.

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Arturo Roca-Rivada, Junior Garcia Oliveira, Eugenia Martin-Vazquez, Alexandra Coomans de Brachène, Xiaoyan Yi, Jose Maria Costa-Júnior, Priscila L Zimath, Flore Van Goethem, François Pattou, Julie Kerr-Conte, Antoine Buemi, Nizar I Mourad, Decio L Eizirik
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引用次数: 0

Abstract

Background: Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known about its complex activation processes and role in the progression of beta cell failure.

Methods: We investigated the IFN-α-stimulated STAT1 pathway from three human beta cell models: EndoC-βH1 cells, iPSC-derived islet-like cells and human islets by directly targeting two T1D candidate genes, namely PTPN2 and BACH2.

Findings: We presently show that PTPN2 and BACH2 modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of CXCL10, but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast but transitory, while STAT1-S727 increases slowly and is associated with the long-term effects of IFN-α exposure.

Interpretation: The present findings provide a better understanding of the dynamics of STAT1 activation in human beta cells and will be useful to develop new and targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases.

Funding: EFSD and Sanofi European Diabetes Research Programme on autoimmunity in type 1 diabetes; Breakthrough T1D, HIRN-CBDS, NIDDK, Fondation Saint-Luc, Programme d'Investissement d'Avenir' to European Genomic Institute for Diabetes, and Fondation de la Recherche Médicale.

1型糖尿病候选基因PTPN2和BACH2调节人β细胞中IFN-α-诱导的JAK/STAT和MAPKs通路之间的串扰。
背景:1型糖尿病(T1D)是一种慢性自身免疫性疾病,导致胰腺β细胞的进行性损失。干扰素(ifn)有助于β细胞自身免疫的启动和扩增。STAT1是IFN信号传导的主要媒介,但对其复杂的激活过程和在β细胞衰竭进展中的作用知之甚少。方法:通过直接靶向两种T1D候选基因PTPN2和BACH2,从EndoC-βH1细胞、ipsc衍生的胰岛样细胞和人胰岛三种人β细胞模型中研究IFN-α刺激的STAT1通路。研究结果:我们目前发现,PTPN2和BACH2通过两种不同的途径调节STAT1的激活,即参与酪氨酸残基磷酸化的JAK/STAT (Y701)和参与丝氨酸残基磷酸化的MAPKs途径(S727)。每种STAT1磷酸化类型都可以独立诱导CXCL10的表达,但这两种残基都是MHC I类分子表达所必需的。IFN-α诱导的STAT1激活是动态和残基依赖性的,STAT1- y701快速但短暂,而STAT1- s727缓慢增加,与IFN-α暴露的长期影响有关。解释:目前的研究结果提供了对人类β细胞中STAT1激活动力学的更好理解,并将有助于开发针对T1D和其他自身免疫性疾病的新的靶向(即偏爱具有特定多态性的个体)疗法。资助:EFSD和赛诺菲欧洲糖尿病研究项目研究1型糖尿病的自身免疫;突破T1D, hrn - cbds, NIDDK, Saint-Luc基金会,欧洲糖尿病基因组研究所的“avenir”投资计划,以及msamdiale研究基金会。
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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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