Department of Biology, Amherst College, Amherst, Massachusetts, USA.
Department of Biology, Amherst College, Amherst, Massachusetts, USA
Appl Environ Microbiol. 2018 Oct 17;84(21). doi: 10.1128/AEM.01113-18. Print 2018 Nov 1.
Acetylation is a broadly conserved mechanism of covalently modifying the proteome to precisely control protein activity. In bacteria, central metabolic enzymes and regulatory proteins, including those involved in virulence, can be targeted for acetylation. In this study, we directly link a putative acetylation system to metabolite-dependent virulence in the pathogen We demonstrate that the and genes, which encode homologs of a deacetylase and an acetyltransferase, respectively, modulate metabolism of acetate, a bacterially derived short-chain fatty acid with important physiological roles in a diversity of host organisms. In , a model arthropod host for infection, the pathogen consumes acetate within the gastrointestinal tract, which contributes to fly mortality. We show that deletion of impairs growth on acetate minimal medium, delays the consumption of acetate from rich medium, and reduces virulence of toward These impacts can be reversed by complementing or by introducing a deletion of into the Δ background. We further show that controls the accumulation of triglycerides in the midgut, which suggests that directly modulates metabolite levels In K-12, is upregulated by cAMP-cAMP receptor protein (CRP), and we identified a similar pattern of regulation in , arguing that the system is activated in response to similar environmental cues. In summary, we demonstrate that proteins likely involved in acetylation can modulate the outcome of infection by regulating metabolite exchange between pathogens and their colonized hosts. The bacterium causes severe disease in humans, and strains can persist in the environment in association with a wide diversity of host species. By investigating the molecular mechanisms that underlie these interactions, we can better understand constraints affecting the ecology and evolution of this global pathogen. The model of infection has revealed that bacterial regulation of acetate and other small metabolites from within the fly gastrointestinal tract is crucial for its virulence. Here, we demonstrate that genes that may modify the proteome of affect virulence toward , most likely by modulating central metabolic pathways that control the consumption of acetate as well as other small molecules. These findings further highlight the many layers of regulation that tune bacterial metabolism to alter the trajectory of interactions between bacteria and their hosts.
乙酰化是一种广泛保守的共价修饰蛋白质组的机制，可精确控制蛋白质活性。在细菌中，中央代谢酶和调节蛋白，包括那些与毒力相关的蛋白，可以被乙酰化靶向。在这项研究中，我们将一个假定的乙酰化系统与病原体中的代谢物依赖性毒力直接联系起来。我们证明，编码去乙酰化酶和乙酰转移酶同源物的 和 基因分别调节 代谢物， 是一种细菌衍生的短链脂肪酸，在多种宿主生物中具有重要的生理作用。在 感染的模式节肢动物宿主中，病原体在胃肠道内消耗乙酸盐，这导致苍蝇死亡。我们表明， 的缺失会损害其在乙酸盐最低培养基上的生长，延迟从丰富培养基中消耗乙酸盐，并降低 对 的毒力。这些影响可以通过补充 或在 Δ背景中引入 缺失来逆转。我们进一步表明， 控制 中甘油三酯的积累，这表明 直接调节代谢物水平。在 K-12 中， 受 cAMP-cAMP 受体蛋白 (CRP) 上调，我们在 中发现了类似的调控模式，这表明该系统在响应类似的环境信号时被激活。总之，我们证明了可能参与乙酰化的蛋白质可以通过调节病原体与其定植宿主之间的代谢物交换来调节感染的结果。细菌 会导致人类严重疾病，并且在与广泛宿主物种相关的环境中可以持续存在。通过研究这些相互作用背后的分子机制，我们可以更好地理解影响这种全球病原体生态和进化的限制因素。 通过 感染模型，我们已经揭示了细菌对来自蝇胃肠道内的乙酸盐和其他小分子的调节对其毒力至关重要。在这里，我们证明，可能修饰 的蛋白质组的基因会影响其对 的毒力，这很可能是通过调节控制乙酸盐以及其他小分子消耗的中心代谢途径来实现的。这些发现进一步强调了调节细菌代谢以改变细菌与其宿主之间相互作用轨迹的许多调控层次。
