The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

中文翻译：

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β-细胞应激通过内质网氨肽酶 1 的转录后调控塑造胰岛素原信号肽的 CTL 免疫识别

前胰岛素原的信号肽是 HLA I 类自身抗原表位的主要来源，这些表位与 1 型糖尿病 (T1D) 中 CD8 T 细胞 (CTL) 介导的 β 细胞破坏有关。其中，发现位于信号肽C末端的10-mer表位在近期发病的T1D患者中最为普遍。虽然信号肽的处理需要信号肽肽酶和内质网 (ER) 氨肽酶 1 (ERAP1) 的联合作用，但控制信号肽修剪的机制和 T1D 炎症环境对这些机制的贡献尚不清楚。这里，我们在人类 β 细胞中表明，ER 应激通过 IRE1α/miR-17-5p 轴在转录后水平调节 ERAP1 基因表达，并证明抑制 IRE1α 活性会损害前胰岛素原信号肽抗原的加工及其在过程中被特定的自身反应性 CTL 识别炎。这些结果强调了内质网应激对 β 细胞对免疫系统可见性增加的影响，并将 IRE1α/miR-17 通路定位为 β 细胞破坏过程的核心成分，并作为治疗自身免疫性 T1D 的潜在靶点.