Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H₂O₂-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1–dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

中文翻译：

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阿那白滞素通过将线粒体氧化还原平衡与自噬耦合来恢复细胞蛋白质稳态

自噬选择性地降解由细胞蛋白质稳态缺陷引起的易于聚集的错误折叠蛋白质。然而，自噬的复杂性可能会阻碍人们充分了解其调节如何用作疾病管理的治疗策略。在这里，我们定义了重组 IL-1 受体拮抗剂（IL-1Ra，阿那白滞素）独立于 IL-1 受体（IL-1R1）影响细胞蛋白质稳态的分子途径。Anakinra 通过涉及芳基烃受体的外源传感途径促进 H 2 O 2 驱动的自噬，该受体通过吲哚胺 2,3-双加氧酶 1-犬尿氨酸途径激活，独立于 IL-1R1 转录激活 NADPH氧化_酶4 _。通过将线粒体氧化还原平衡与自噬结合起来，阿那白滞素改善了小鼠和人类囊性纤维化中失调的蛋白质稳态网络。我们预计，阿那白滞素除了具有 IL-1R1 依赖性抗炎特性外，还可能代表一种治疗选择，它可以作用于线粒体氧化应激和自噬的交叉点，并具有恢复蛋白质稳态缺陷导致人类疾病的能力。