Long RNA Sequencing and Ribosome Profiling of Inflamed β-Cells Reveal an Extensive Translatome Landscape
Long RNA Sequencing and Ribosome Profiling of Inflamed β-Cells Reveal an Extensive Translatome Landscape
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DOI：
10.2337/db20-1122
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发表时间：
2021-10-01
期刊：
影响因子：
7.7
通讯作者：
Zaldumbide, Arnaud
中科院分区：
文献类型：
--
作者：
Thomaidou, Sofia;Slieker, Roderick C.;Zaldumbide, Arnaud
1型糖尿病（T1D）是一种自身免疫性疾病，其特征在于自身反应性T细胞介导的产生胰岛素的胰腺β细胞的破坏。越来越多的证据表明，β细胞本身通过产生逃避中枢耐受的异常或修饰的蛋白质而产生新抗原，从而有助于其自身的破坏。我们最近证明，应激放大的核糖体不忠实性可能导致人类β细胞中新抗原的产生，强调了非常规翻译事件在自身免疫中的参与，如在癌症或病毒感染的组织中发生的。使用全转录组分析方法来映射标准和炎症条件下人β细胞中的翻译起始起始位点，我们鉴定了一组全新的多肽，其来源于长非编码RNA内的非经典起始位点和翻译起始。我们的数据强调了β细胞翻译组的极端多样性，并可能揭示β细胞窘迫、疾病预测和进展以及T1D治疗干预的新功能生物标志物。
Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of the insulin-producing pancreatic beta -cells. Increasing evidence suggest that the beta -cells themselves contribute to their own destruction by generating neoantigens through the production of aberrant or modified proteins that escape central tolerance. We recently demonstrated that ribosomal infidelity amplified by stress could lead to the generation of neoantigens in human beta -cells, emphasizing the participation of nonconventional translation events in autoimmunity, as occurring in cancer or virus-infected tissues. Using a transcriptome-wide profiling approach to map translation initiation start sites in human beta -cells under standard and inflammatory conditions, we identify a completely new set of polypeptides derived from noncanonical start sites and translation initiation within long noncoding RNA. Our data underline the extreme diversity of the beta -cell translatome and may reveal new functional biomarkers for beta -cell distress, disease prediction and progression, and therapeutic intervention in T1D.