Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom.
Front Endocrinol (Lausanne). 2021 Mar 8;12:625235. doi: 10.3389/fendo.2021.625235. eCollection 2021.
Mounting evidence suggests a role for alternative splicing (AS) of transcripts in the normal physiology and pathophysiology of the pancreatic β-cell. In the apparent absence of RNA repair systems, RNA decay pathways are likely to play an important role in controlling the stability, distribution and diversity of transcript isoforms in these cells. Around 35% of alternatively spliced transcripts in human cells contain premature termination codons (PTCs) and are targeted for degradation nonsense-mediated decay (NMD), a vital quality control process. Inflammatory cytokines, whose levels are increased in both type 1 (T1D) and type 2 (T2D) diabetes, stimulate alternative splicing events and the expression of NMD components, and may or may not be associated with the activation of the NMD pathway. It is, however, now possible to infer that NMD plays a crucial role in regulating transcript processing in normal and stress conditions in pancreatic β-cells. In this review, we describe the possible role of Regulated Unproductive Splicing and Translation (RUST), a molecular mechanism embracing NMD activity in relationship to AS and translation of damaged transcript isoforms in these cells. This process substantially reduces the abundance of non-functional transcript isoforms, and its dysregulation may be involved in pancreatic β-cell failure in diabetes.
越来越多的证据表明，转录本的选择性剪接（AS）在胰腺 β 细胞的正常生理和病理生理中起作用。在似乎缺乏 RNA 修复系统的情况下，RNA 衰变途径可能在控制这些细胞中转录本异构体的稳定性、分布和多样性方面发挥重要作用。在人类细胞中，大约 35%的选择性剪接转录本含有终止密码子（PTCs），并被靶向降解 无意义介导的衰变（NMD），这是一个重要的质量控制过程。炎症细胞因子在 1 型（T1D）和 2 型（T2D）糖尿病中水平升高，刺激选择性剪接事件和 NMD 成分的表达，可能与 NMD 途径的激活有关，也可能无关。然而，现在可以推断，NMD 在调节胰腺 β 细胞正常和应激条件下的转录本处理中起着至关重要的作用。在这篇综述中，我们描述了调控非生产性剪接和翻译（RUST）的可能作用，这是一种分子机制，将 NMD 活性与 AS 和这些细胞中受损转录本异构体的翻译联系起来。这个过程大大降低了无功能转录本异构体的丰度，其失调可能与糖尿病中胰腺 β 细胞衰竭有关。
