Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to β cell failure.

中文翻译：

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Translocon Declogger Ste24可以防止IAPP寡聚物引起的蛋白毒性。

人们认为2型糖尿病（T2D）患者胰腺中的人类胰岛淀粉样多肽（IAPP）聚集体会导致β细胞功能障碍和死亡。为了了解IAPP如何伤害细胞以及如何克服这种情况，我们创建了IAPP毒性的酵母模型。Ste24是一种进化上保守的蛋白酶，最近被报道可以降解卡在胞质和内质网之间的转运子中的肽，是IAPP毒性的最强抑制剂。通过测试具有不同活性水平的人类同源物ZMPSTE24的变体，证明了IAPP毒性的挽救与降糖效率成正比。使用酵母模型表征了在来自T2D患者的最大外显子组序列数据库中鉴定出的临床相关ZMPSTE24变体，揭示了14个部分功能丧失的变体，这些变体在糖尿病患者中富集了2倍以上。因此，IAPP寡聚物堵塞转位子可能导致β细胞衰竭。