Crosstalk between guanosine nucleotides regulates cellular heterogeneity in protein synthesis during nutrient limitation.
Crosstalk between guanosine nucleotides regulates cellular heterogeneity in protein synthesis during nutrient limitation.
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DOI：
10.1371/journal.pgen.1009957
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发表时间：
2022-05
期刊：
影响因子：
4.5
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中科院分区：
文献类型：
--
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微生物种群的表型异质性可以通过产生可能在未来环境中具有不同适应性的细胞亚群来促进动态环境中的生存。经历营养限制的枯草芽孢杆菌培养物含有表现出相对高或低蛋白质合成活性的不同细胞亚群。这种异质性需要通过三种酶：SasA、SasB和RelA产生磷酸化鸟苷核苷酸（pp）pGpp。在这里，我们表明，这些酶差异影响这种双峰：RelA和SasB是必要的，以产生亚群的细胞表现出低蛋白质合成，而SasA是必要的，以产生细胞表现出相对较高的蛋白质合成。以前，据报道，RelA产品变构激活SasB，我们发现SasA产品竞争性抑制这种激活。最后，我们提供了体内证据表明，这种拮抗作用介导了所观察到的蛋白质合成的异质性。因此，这项工作确定了蛋白质合成表型异质性的机制。在遇到不利于生长的条件（例如营养限制）时，细菌进入由鸟苷核苷酸组（统称为（pp）pGpp）介导的静止表型。这些核苷酸指导能量密集型过程的下调，并且对于在退出快速生长期间观察到的蛋白质合成中的显著异质性是必不可少的。在这里，我们表明，（pp）pGpp激酶的网络是负责这种异质性，并描述了一种机制，允许整合多个信号的决定下调细胞中最能量密集的过程。
Phenotypic heterogeneity of microbial populations can facilitate survival in dynamic environments by generating sub-populations of cells that may have differential fitness in a future environment. Bacillus subtilis cultures experiencing nutrient limitation contain distinct sub-populations of cells exhibiting either comparatively high or low protein synthesis activity. This heterogeneity requires the production of phosphorylated guanosine nucleotides (pp)pGpp by three synthases: SasA, SasB, and RelA. Here we show that these enzymes differentially affect this bimodality: RelA and SasB are necessary to generate the sub-population of cells exhibiting low protein synthesis whereas SasA is necessary to generate cells exhibiting comparatively higher protein synthesis. Previously, it was reported that a RelA product allosterically activates SasB and we find that a SasA product competitively inhibits this activation. Finally, we provide in vivo evidence that this antagonistic interaction mediates the observed heterogeneity in protein synthesis. This work therefore identifies the mechanism underlying phenotypic heterogeneity in protein synthesis. Upon encountering conditions unfavorable to growth such as nutrient limitation, bacteria enter a quiescent phenotype that is mediated by group of guanosine nucleotides collectively known as (pp)pGpp. These nucleotides direct the down-regulation of energy intensive processes and are essential for a striking heterogeneity in protein synthesis observed during exit from rapid growth. Here, we show that a network of (pp)pGpp synthases is responsible for this heterogeneity and describe a mechanism that allows for the integration of multiple signals into the decision to down regulate the most energy intensive process in a cell.
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