ADAR1-dependent editing regulates human β cell transcriptome diversity during inflammation.
ADAR1-dependent editing regulates human β cell transcriptome diversity during inflammation.
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DOI：
10.3389/fendo.2022.1058345
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发表时间：
2022
影响因子：
5.2
通讯作者：
Zaldumbide, Arnaud
中科院分区：
文献类型：
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作者：
Szymczak, Florian;Cohen-Fultheim, Roni;Thomaidou, Sofia;de Brachene, Alexandra Coomans;Castela, Angela;Colli, Maikel;Marchetti, Piero;Levanon, Erez;Eizirik, Decio;Zaldumbide, Arnaud
肠道病毒感染长期以来一直被怀疑是1型糖尿病的可能诱因。在感染时，病毒双链RNA（dsRNA）被膜和胞质传感器识别，所述膜和胞质传感器协调I型干扰素信号传导和先天免疫细胞向胰岛的募集。在这种情况下，腺苷脱氨酶作用于RNA 1（ADAR 1）编辑通过诱导腺苷错配，使RNA双链体不稳定，从而防止过度的免疫激活，在抑制免疫应答中发挥重要作用。使用来自暴露于IFNα或IFNγ/IL 1 β的人胰岛和EndoC-βH1细胞的高通量RNA测序数据，我们评估了ADAR 1在人胰腺β细胞中的作用，并确定了1型糖尿病病理生理环境对ADAR 1依赖性RNA编辑的影响。我们发现，IFNα和IFNγ/IL 1 β刺激均促进ADAR 1表达，并增加EndoC-βH1细胞和原代人胰岛中含ADAR mRNA的A至I RNA编辑。我们证明，ADAR 1过表达抑制I型干扰素应答信号，而ADAR 1沉默增强IFNα效应。此外，ADAR 1过表达触发了选择性剪接mRNA的产生，突出了ADAR 1在炎症条件下作为β细胞转录组调节因子的新作用。
Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation. Using high-throughput RNA sequencing data from human islets and EndoC-βH1 cells exposed to IFNα or IFNγ/IL1β, we evaluated the role of ADAR1 in human pancreatic β cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing. We show that both IFNα and IFNγ/IL1β stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-βH1 cells as well as in primary human islets. We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFNα effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the β cell transcriptome under inflammatory conditions.
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影响因子：
5.2
作者：
Colli ML;Szymczak F;Eizirik DL
通讯作者：
Eizirik DL
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影响因子：
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作者：
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
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作者：
Nguyen H;Guyer P;Ettinger RA;James EA
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