Integrated Cardio Metabolic Centre (ICMC), Department of Medicine, Karolinska Institute, Blickagången 6, 14157, Huddinge, Sweden.
Department of Biosciences and Nutrition, Karolinska Institute, Blickagången 16, 14157, Huddinge, Sweden.
Nat Commun. 2018 Oct 23;9(1):4400. doi: 10.1038/s41467-018-06624-0.
The ability to perceive and respond to harmful conditions is crucial for the survival of any organism. The transcription factor DAF-16/FOXO is central to these responses, relaying distress signals into the expression of stress resistance and longevity promoting genes. However, its sufficiency in fulfilling this complex task has remained unclear. Using C. elegans, we show that DAF-16 does not function alone but as part of a transcriptional regulatory module, together with the transcription factor HLH-30/TFEB. Under harmful conditions, both transcription factors translocate into the nucleus, where they often form a complex, co-occupy target promoters, and co-regulate many target genes. Interestingly though, their synergy is stimulus-dependent: They rely on each other, functioning in the same pathway, to promote longevity or resistance to oxidative stress, but they elicit heat stress responses independently, and they even oppose each other during dauer formation. We propose that this module of DAF-16 and HLH-30 acts by combinatorial gene regulation to relay distress signals into the expression of specific target gene sets, ensuring optimal survival under each given threat.
感知和应对有害条件的能力对任何生物体的生存都是至关重要的。转录因子 DAF-16/FOXO 是这些反应的核心，将应激信号传递到应激抗性和长寿促进基因的表达中。然而，其在完成这一复杂任务中的充分性仍然不清楚。使用秀丽隐杆线虫，我们表明 DAF-16 不是单独发挥作用，而是作为转录调控模块的一部分，与转录因子 HLH-30/TFEB 一起发挥作用。在有害条件下，这两个转录因子都易位到细胞核中，在那里它们经常形成复合物，共同占据靶启动子，并共同调节许多靶基因。有趣的是，它们的协同作用是刺激依赖性的：它们相互依赖，在同一途径中发挥作用，以促进长寿或对氧化应激的抗性，但它们独立地引发热应激反应，甚至在 dauer 形成过程中相互对抗。我们提出，DAF-16 和 HLH-30 这一模块通过组合基因调控来传递应激信号，将其表达为特定的靶基因集，以确保在每种特定威胁下的最佳生存。
