The archipelago ubiquitin ligase subunit acts in target tissue to restrict tracheal terminal cell branching and hypoxic-induced gene expression.
The archipelago ubiquitin ligase subunit acts in target tissue to restrict tracheal terminal cell branching and hypoxic-induced gene expression.
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DOI：
10.1371/journal.pgen.1003314
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Moberg KH
中科院分区：
文献类型：
--
作者：
Mortimer NT;Moberg KH
黑腹果蝇基因群岛（ago）编码SCF（Skp/Cullin/F-box）型多聚泛素连接酶的F-box/WD-重复蛋白底物特异性因子，该连接酶通过靶向蛋白质被蛋白酶体降解来抑制肿瘤样生长。Ago蛋白在蝇胚胎和幼虫中广泛表达，并促进有丝分裂活性细胞中促增殖蛋白的降解。然而，在有丝分裂后发育过程中对Ago的需求仍然在很大程度上未被探索。在这里，我们表明，阿戈是一种拮抗剂的生理反应，低氧（缺氧）。在常氧条件下，降低幼虫肌细胞中Ago活性可增强附近气管末端细胞的分支。这种气管生成表型显示出对sima的遗传依赖性，sima编码缺氧诱导转录因子dHIF的HIF-1α亚基，其靶点是FGF配体无分支（bnl），并且通过耗尽果蝇Von Hippel Lindau（dVHL）因子而增强，dVHL因子是一种氧依赖性泛素连接酶的亚基，可降解后生动物细胞中的Sima/HIF-1α蛋白。遗传减少ago的结果在组成型表达的一些缺氧诱导基因在常氧，增加其他人的敏感性，以轻度缺氧刺激，并提高成年苍蝇的能力，从缺氧昏迷恢复。作为与这些遗传数据相关的分子，我们发现Ago与Sima物理关联并限制体内Sima水平。总的来说，这些研究结果确定Ago作为一个电路，抑制幼虫肌细胞的气管活性拮抗西玛介导的转录反应缺氧所需的元素。多细胞动物的细胞必须适应不断变化的环境条件，以确保更大的生物体的生存。他们面临的一个关键挑战是溶解氧可用性的波动。当细胞缺氧时，它们通过启动一个帮助它们生存的基因表达程序来做出反应。这个程序的关键是一种蛋白质，在人类中称为HIF-1α，在果蝇中称为Sima（或Sima），在正常氧下保持不活动，但在缺氧时被激活。负责这种转换的机制尚未完全了解。在这项研究中，我们提出了遗传和分子证据，证明蛋白质降解机制的一个组成部分称为Archipelago是保持西玛在发育中的肌肉细胞不活跃所必需的，并且遗传去除Archipelago使这些细胞“认为”它们是缺氧的。这一发现和支持它的数据为细胞用来控制其对氧气水平变化的反应的遗传电路提供了新的见解，并表明氧稳态的缺陷可能导致与人类相当于群岛的Fbw 7丢失相关的癌症疾病状态。
The Drosophila melanogaster gene archipelago (ago) encodes the F-box/WD-repeat protein substrate specificity factor for an SCF (Skp/Cullin/F-box)-type polyubiquitin ligase that inhibits tumor-like growth by targeting proteins for degradation by the proteasome. The Ago protein is expressed widely in the fly embryo and larva and promotes degradation of pro-proliferative proteins in mitotically active cells. However the requirement for Ago in post-mitotic developmental processes remains largely unexplored. Here we show that Ago is an antagonist of the physiologic response to low oxygen (hypoxia). Reducing Ago activity in larval muscle cells elicits enhanced branching of nearby tracheal terminal cells in normoxia. This tracheogenic phenotype shows a genetic dependence on sima, which encodes the HIF-1α subunit of the hypoxia-inducible transcription factor dHIF and its target the FGF ligand branchless (bnl), and is enhanced by depletion of the Drosophila Von Hippel Lindau (dVHL) factor, which is a subunit of an oxygen-dependent ubiquitin ligase that degrades Sima/HIF-1α protein in metazoan cells. Genetic reduction of ago results in constitutive expression of some hypoxia-inducible genes in normoxia, increases the sensitivity of others to mild hypoxic stimulus, and enhances the ability of adult flies to recover from hypoxic stupor. As a molecular correlate to these genetic data, we find that Ago physically associates with Sima and restricts Sima levels in vivo. Collectively, these findings identify Ago as a required element of a circuit that suppresses the tracheogenic activity of larval muscle cells by antagonizing the Sima-mediated transcriptional response to hypoxia. Cells in multicellular animals must adapt to changing environmental conditions in order to ensure survival of the larger organism. One key challenge they face is fluctuation in the availability of dissolved oxygen. As cells get low on oxygen, they respond by turning on a program of gene expression that helps them survive. The key to this program is a protein, called HIF-1α in humans and Similar (or Sima) in the fruit fly Drosophila melanogaster, that is kept inactive in normoxia but is activated in hypoxia. The mechanisms responsible for this switch are not completely understood. In this study, we present genetic and molecular evidence that a component of the protein degradation machinery called Archipelago is required to keep Sima inactive in developing muscle cells and that genetically removing Archipelago makes these cells “think” they are hypoxic. This finding and the data that support it provide new insight into genetic circuits that cells use to control their response to changing oxygen levels and suggest that defects in oxygen homeostasis may contribute to cancerous disease states associated with loss of the human equivalent of Archipelago called Fbw7.
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