MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research.
MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research.
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DOI：
10.1530/eje-15-0916
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发表时间：
2016-05
影响因子：
5.8
通讯作者：
Eizirik DL
中科院分区：
文献类型：
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作者：
Juan-Mateu J;Villate O;Eizirik DL
1型糖尿病（T1 D）是一种慢性自身免疫性疾病，其中胰腺β细胞被浸润的免疫细胞和这些细胞释放的细胞因子杀死。这发生在入侵的免疫细胞和靶β细胞之间的失调对话的背景下，但决定β细胞命运的细胞内信号仍有待澄清。选择性剪接（alternative splicing，AS）是影响基因表达的一种复杂的转录后调控机制。它调节成熟mRNA中外显子的包含/排除，允许单个基因产生多种蛋白质异构体，从而扩大蛋白质组多样性。功能相关的转录物群体通过主剪接因子协调剪接，定义了允许细胞响应于细胞内和细胞外线索而快速适应其转录组的调控网络。人们对AS在自身免疫性疾病中的作用越来越感兴趣，但对其在T1 D中的作用知之甚少。在这篇综述中，我们讨论了最近的研究结果表明，剪接事件发生在免疫和胰腺β细胞有助于T1 D的发病机制。T细胞和淋巴结基质细胞中的剪接开关参与调节针对辟田胞的免疫应答，而暴露于促炎性细胞因子的辟田胞激活复杂的剪接网络，所述剪接网络调节辟田胞活力、新抗原的表达和对免疫诱导的应激的易感性。揭示AS在β细胞功能丧失和死亡中的作用将增加我们对T1 D发病机制的理解，并可能为疾病预防和治疗开辟新的途径。
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in Tcells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.