FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells
FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells
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DOI：
10.1371/journal.pgen.1008097
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发表时间：
2019-04-01
期刊：
影响因子：
4.5
通讯作者：
Webb, Ashley E.
中科院分区：
文献类型：
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作者：
Audesse, Amanda J.;Dhakal, Shleshma;Webb, Ashley E.
维持健康的蛋白质组对于细胞内稳态是必不可少的，蛋白质稳态的丧失与组织功能障碍和神经退行性疾病相关。支持健康细胞中蛋白质稳态的机制以及它们在衰老或疾病状态下如何变得有缺陷还没有完全了解。在这里，我们调查的转录程序，是必不可少的神经干细胞和祖细胞（NSPC）的功能，并发现一个程序的自噬基因的转录因子FOXO 3的控制下。使用基因组方法，我们观察到FOXO3直接结合参与自噬的成人NSPCs中的靶基因网络，并发现FOXO3在功能上调节这些细胞中自噬的诱导。有趣的是，在没有FOXO活性的情况下，聚集体在NSPCs中积累，并且这种作用被TOR（雷帕霉素靶点）抑制逆转。令人惊讶的是，增强FOXO 3导致蛋白质聚集体的成核，但不增加其降解。这里介绍的工作确定了一个基因组网络的直接控制下的一个关键的转录调节衰老是至关重要的维持健康的哺乳动物干细胞池，以支持终身neurogenes.Author摘要蛋白质聚集体的积累是有害的细胞功能，并可能导致神经退行性疾病。健康的细胞使用一种称为自噬的过程来降解聚集体，并根据需要去除受损的蛋白质和细胞器。这一过程在干细胞中尤为重要，因为干细胞必须清除受损的细胞物质，以防止其遗传到后代。控制干细胞自噬总体水平的机制还不清楚。在这里，我们表明，转录调节因子FOXO 3，这是支持干细胞功能的关键，调节小鼠神经干细胞和祖细胞的自噬基因的基因组网络。我们发现FOXO 3作为一个开关，诱导干细胞自噬的功能，它的活性是必需的，以抑制聚集在这些细胞。这项工作是第一个阐明神经干细胞中促进聚集体清除的基因组程序。了解干细胞如何维持蛋白质质量控制对于使用再生医学来理解和治疗与年龄相关的疾病和退行性疾病具有重要意义。
Maintenance of a healthy proteome is essential for cellular homeostasis and loss of proteostasis is associated with tissue dysfunction and neurodegenerative disease. The mechanisms that support proteostasis in healthy cells and how they become defective during aging or in disease states are not fully understood. Here, we investigate the transcriptional programs that are essential for neural stem and progenitor cell (NSPC) function and uncover a program of autophagy genes under the control of the transcription factor FOXO3. Using genomic approaches, we observe that FOXO3 directly binds a network of target genes in adult NSPCs that are involved in autophagy, and find that FOXO3 functionally regulates induction of autophagy in these cells. Interestingly, in the absence of FOXO activity, aggregates accumulate in NSPCs, and this effect is reversed by TOR (target of rapamycin) inhibition. Surprisingly, enhancing FOXO3 causes nucleation of protein aggregates, but does not increase their degradation. The work presented here identifies a genomic network under the direct control of a key transcriptional regulator of aging that is critical for maintaining a healthy mammalian stem cell pool to support lifelong neurogenesis.Author summary The buildup of protein aggregates is deleterious to cellular function and can cause neurodegenerative disease. Healthy cells use a process known as autophagy to degrade aggregates and remove damaged proteins and organelles as needed. This process is particularly important in stem cells, which must clear damaged cellular material to prevent its inheritance down the lineage. The mechanisms that control overall levels of autophagy in stem cells are not well understood. Here, we show that a transcriptional regulator, FOXO3, which is critical for supporting stem cell functionality, regulates a genomic network of autophagy genes in mouse neural stem and progenitor cells. We find that FOXO3 functions as a switch to induce autophagy in stem cells, and that its activity is required to restrain aggregate accumulation in these cells. This work is the first to elucidate a genomic program in neural stem cells that promotes aggregate clearance. Understanding how stem cells maintain protein quality control has important implications for using regenerative medicine to understand and treat age-related and degenerative diseases.