Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator.
Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator.
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DOI：
10.1371/journal.pbio.0060233
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发表时间：
2008-09-30
期刊：
影响因子：
9.8
通讯作者：
Lee SS
中科院分区：
文献类型：
--
作者：
Li J;Ebata A;Dong Y;Rizki G;Iwata T;Lee SS
转录因子FOXO-16/forkhead box O（FOXO）是多种生物体中的关键寿命决定因子，然而其转录活性如何调节的分子基础在很大程度上仍然未知。我们报告说，秀丽隐杆线虫同源宿主细胞因子1（HCF-1）代表了一种新的长寿调制器和功能作为负调节剂的β-16。in C. hcf-1失活导致daf-16依赖性寿命延长高达40%，并提高了对特定应激刺激的抵抗力。HCF-1显示出普遍存在的核定位，并与α-16物理相关。此外，hcf-1的缺失导致了hcf-16向其靶基因启动子的募集增加，并改变了hcf-16调控基因的一个子集的表达。我们认为HCF-1调节C.线虫的长寿和应激反应，通过与α-淀粉酶-16形成复合物，并限制α-淀粉酶-16的一部分进入其靶基因启动子，从而调节α-淀粉酶-16介导的选择性靶基因的转录。由于HCF-1是高度保守的，我们的研究结果对哺乳动物的衰老和FOXO调控具有重要意义。在进化上多样的生物体中，调节寿命的关键分子之一是转录因子β 16/FOXO。尽管它在衰老和其他生物学过程中的重要性，但在细胞核中如何调节β-16/FOXO活性在很大程度上是未知的。我们报告了一个新的球员重要的老化调制，线虫同源的宿主细胞因子1（HCF-1），并表明它的功能作为负调节剂的β-16。在蠕虫中，HCF-1失活可将寿命延长40%，并增加对特定应激刺激的抵抗力。为了影响寿命和应激反应，HCF-1需要β-16的活性。我们发现，HCF-1蛋白在细胞核中表达，并与蠕虫中的HCF-16结合。此外，我们证明，HCF-1的损失导致在其靶基因的启动子和改变的表达的一个子集的histogram-16调节基因的水平升高。我们认为HCF-1通过与转录因子β-16结合并阻止转录因子进入其靶基因启动子，从而调节β-16靶基因的表达来调节寿命和应激反应。由于HCF-1是高度保守的，我们的研究结果对人类的衰老和FOXO调控具有重要意义。秀丽隐杆线虫HCF-1是一种新的长寿因子，其功能是通过与β-16/FOXO形成复合物并阻止β-16/FOXO的一部分进入其靶基因启动子来拮抗β-16/FOXO的转录活性。
The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals. One of the key molecules that modulate longevity in evolutionarily diverse organisms is the transcription factor DAF-16/FOXO. Despite its importance in aging and other biological processes, how DAF-16/FOXO activity is regulated in the nucleus is largely unknown. We report a new player important for aging modulation, the nematode homolog of host cell factor 1 (HCF-1), and show that it functions as a negative regulator of DAF-16. In worms, HCF-1 inactivation extends lifespan up to 40% and increases resistance to specific stress stimuli. To affect lifespan and stress response, HCF-1 requires the activity of DAF-16. We show that the HCF-1 protein is expressed in the nucleus and partners with DAF-16 in worms. Furthermore, we demonstrate that loss of HCF-1 results in elevated levels of DAF-16 at the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates longevity and stress response by binding to DAF-16 and preventing the transcription factor from accessing its target gene promoters, thereby regulating the expression of DAF-16 target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in humans. Caenorhabditis elegans HCF-1 is a new longevity factor that functions to antagonize the transcriptional activities of DAF-16/FOXO by forming a complex with DAF-16/FOXO and preventing a fraction of DAF-16/FOXO from accessing its target gene promoters.
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