The cvn8 Conservon System Is a Global Regulator of Specialized Metabolism in Streptomyces coelicolor during Interspecies Interactions.
The cvn8 Conservon System Is a Global Regulator of Specialized Metabolism in Streptomyces coelicolor during Interspecies Interactions.
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DOI：
10.1128/msystems.00281-21
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发表时间：
2021-10-26
期刊：
影响因子：
6.4
通讯作者：
Traxler MF
中科院分区：
文献类型：
--
作者：
Bonet B;Ra Y;Cantu Morin LM;Soto Bustos J;Livny J;Traxler MF
已知种间相互作用可激活不同放线菌的特殊代谢。然而，物种间的信号是如何被感知并最终导致诱导专门的代谢物生物合成基因簇的，在很大程度上仍未被探索。利用转录组测序（RNA-seq），我们分析了模型放线菌在与四种不同放线菌相互作用过程中转录诱导的基因，包括编码异常调控系统的基因，称为保守子。在这样一个由cvn8基因编码的系统中，缺失导致S. coelicolor在相互作用过程中产生色素抗生素的模式发生改变。进一步的转录组学分析表明，突变体缺乏cvn8位点上的五个基因，该系统是至少四种不同的特化代谢物生物合成途径的全球调节剂。保守系统如何在机制水平上调节基因表达尚不清楚，尽管已经假设它们可能以类似于真核g蛋白偶联受体的方式起作用。本文提供的数据表明，cvnA8和cvnF8 （SCO6939）基因的基因产物可能在Cvn8信号级联的一部分中一起起作用，而cvnC8和cvnD8基因产物可能在另一部分中一起起作用。重要的是，由于cvnD8可能编码一种类似ras的GTPase，这些结果将g蛋白介导的信号传导与细菌中的基因调控联系起来。此外，任何一个cvn8基因的缺失都会导致邻近的一个隐藏的蓝肽生物合成基因簇的异常高表达，这表明保守系统可能是激活沉默的特化代谢物生物合成途径的有效靶点。重要性不同种类放线菌细菌之间的相互作用通常会触发其中一种菌株产生特殊的代谢物，如抗生素。然而，这种诱导是如何在遗传水平上发生的，人们知之甚少。利用转录组学方法，我们发现了一个不寻常的调节系统，即保守系统，在相互作用过程中负责调节有机链霉菌多种特殊代谢物生物合成基因簇的表达。保护系统是不寻常的，因为它们似乎使用小的gtp酶作为其信号级联的重要组成部分。小GTPase在真核生物信号通路中很常见，但这里提出的结果是值得注意的，因为它们暗示了一个包含小GTPase的系统在细菌的全局基因调控中。缺乏这种保守系统的突变体也表现出异常高表达的基因簇，这些基因簇参与了一种未知的特殊代谢物的产生，这表明保守突变体可能有助于推动天然产物的发现。
Interspecies interactions are known to activate specialized metabolism in diverse actinomycetes. However, how interspecies cues are sensed and ultimately lead to induction of specialized metabolite biosynthetic gene clusters remains largely unexplored. Using transcriptome sequencing (RNA-seq), we analyzed genes that were transcriptionally induced in the model actinomycete Streptomyces coelicolor during interactions with four different actinomycetes, including genes that encode unusual regulatory systems known as conservons. Deletions in one such system, encoded by the cvn8 genes, led to altered patterns of pigmented antibiotic production by S. coelicolor during interactions. Further transcriptomic analysis of mutants lacking each of the five genes in the cvn8 locus demonstrated that this system is a global regulator of at least four different specialized metabolite biosynthetic pathways. How conservon systems work at the mechanistic level to regulate gene expression is not well understood, although it has been hypothesized that they may function in a way similar to eukaryotic G-protein-coupled receptors. The data presented here indicate that the gene products of the cvnA8 and cvnF8 (SCO6939) genes likely function together in one part of the Cvn8 signaling cascade, while the cvnC8 and cvnD8 gene products likely function together in another part. Importantly, because cvnD8 likely encodes a Ras-like GTPase, these results connect G-protein-mediated signaling to gene regulation in a bacterium. Additionally, deletion of any of the cvn8 genes led to abnormally high expression of an adjacent cryptic lanthipeptide biosynthetic gene cluster, indicating that conservon systems may be fruitful targets for manipulation to activate silent specialized metabolite biosynthetic pathways. IMPORTANCE Interactions between different species of actinomycete bacteria often trigger one of the strains to produce specialized metabolites, such as antibiotics. However, how this induction occurs at the genetic level is poorly understood. Using transcriptomic methods, we show that an unusual regulatory system, known as a conservon system, is responsible for regulating expression of multiple specialized metabolite biosynthetic gene clusters in the organism Streptomyces coelicolor during interactions. Conservon systems are unusual because they appear to employ small GTPases as an important component of their signaling cascades. Small GTPases are common in eukaryotic signaling pathways, but the results presented here are notable since they implicate a system that includes a small GTPase in global gene regulation in a bacterium. Mutants lacking this conservon system also showed abnormally high expression of a gene cluster involved in making an unknown specialized metabolite, suggesting that conservon mutants might be useful for driving natural product discovery.