Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant INS gene–induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.

中文翻译：

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胰岛素原自相关在突变 INS 基因诱导的青年糖尿病中的作用

内质网 (ER) 中错误折叠的突变体和野生型 (WT) 胰岛素原 (PI) 之间的异常相互作用驱动突变 INS 基因诱导的青年糖尿病 (MIDY) 的分子发病机制。这些异常交互是如何启动的仍然未知。通常，PI-WT 在 ER 中二聚化。在这里，我们建议正常的 PI-PI 接触面，涉及 B 链，有助于错误折叠的 MIDY 突变体的显性负效应。具体来说，我们发现 PI B 链酪氨酸 16 (Tyr-B16) 是正常 PI 二聚化中的关键残基，有助于赋予 MIDY 突变体 PI-C(A7)Y 显性失活行为。在 PI-C(A7)Y 中用 Ala、Asp 或 Pro 替代 Tyr-B16 会减少 MIDY 突变体和 PI-WT 之间的异常相互作用，从而挽救 PI-WT 输出，限制 ER 应激，增加 β 细胞和人类胰岛中的胰岛素产量。这项研究揭示了第一个证据表明非共价 PI-PI 接触启动错误折叠 PI 的显性负性行为，指向一个新的治疗靶点来增强 PI-WT 输出和增加胰岛素产生。