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首页> 外文期刊>Cell metabolism >The FOXO transcription factor DAF-16 bypasses ire-1 requirement to promote endoplasmic reticulum homeostasis
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The FOXO transcription factor DAF-16 bypasses ire-1 requirement to promote endoplasmic reticulum homeostasis

机译：FOXO转录因子DAF-16绕过ire-1的要求，以促进内质网稳态

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摘要

The unfolded protein response (UPR) allows cells to adjust the capacity of the endoplasmic reticulum (ER) to the load of ER-associated tasks. We show that activation of the Caenorhabditis elegans transcription factor DAF-16 and its human homolog FOXO3 restore secretory protein metabolism when the UPR is dysfunctional. We show that DAF-16 establishes alternative ER-associated degradation systems that degrade misfolded proteins independently of the ER stress sensor ire-1 and the ER-associated E3 ubiquitin ligase complex sel-11/sel-1. This is achieved by enabling autophagy-mediated degradation and by increasing the levels of skr-5, a component of an ER-associated ubiquitin ligase complex. These degradation systems can act together with the conserved UPR to improve ER homeostasis and ER stress resistance, beyond wild-type levels. Because there is no sensor in the ER that activates DAF-16 in response to intrinsic ER stress, natural or artificial interventions that activate DAF-16 may be useful therapeutic approaches to maintain ER homeostasis.
机译：展开的蛋白质反应（UPR）使细胞可以调节内质网（ER）的能力，以适应与ER相关的任务。我们显示激活的秀丽隐杆线虫转录因子DAF-16和其人类同源物FOXO3的UPR功能障碍时恢复分泌蛋白代谢。我们显示DAF-16建立了替代ER相关的降解系统，可独立于ER应激传感器ire-1和ER相关的E3泛素连接酶复合体sel-11 / sel-1降解错误折叠的蛋白质。这是通过实现自噬介导的降解和增加skr-5（一种与ER相关的泛素连接酶复合物的成分）的水平来实现的。这些降解系统可以与保守的UPR一起发挥作用，以改善ER稳态和ER胁迫抗性，使其超过野生型水平。由于ER中没有传感器响应内在的ER应激而激活DAF-16，因此激活DAF-16的自然或人工干预可能是维持ER稳态的有用治疗方法。

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