A Putative Acetylation System in Vibrio cholerae Modulates Virulence in Arthropod Hosts
A Putative Acetylation System in Vibrio cholerae Modulates Virulence in Arthropod Hosts
复制标题
DOI：
10.1128/aem.01113-18
复制
发表时间：
2018-08
影响因子：
4.4
通讯作者：
K. Liimatta;Emily Flaherty;Gabby Ro;D. Nguyen;C. Prado;A. Purdy
中科院分区：
文献类型：
--
作者：
K. Liimatta;Emily Flaherty;Gabby Ro;D. Nguyen;C. Prado;A. Purdy
霍乱弧菌在人类中会导致严重的疾病，并且菌株可以在环境中与广泛多样性的宿主物种相关联。通过研究这些相互作用的分子机制，我们可以更好地了解影响这种全球病原体的生态和进化的制约因素。感染霍乱弧菌的果蝇模型表明，苍蝇胃肠道内醋酸盐和其他小代谢物的细菌调节对其毒力至关重要。在这里，我们证明了可能改变霍乱弧菌蛋白质组的基因影响对果蝇的毒力，最有可能的是通过调节控制醋酸盐和其他小分子消耗的中心代谢途径。这些发现进一步突显了调节细菌新陈代谢的多个层面，以改变细菌与宿主之间的相互作用轨迹。摘要乙酰化是一种广泛保守的共价修饰蛋白质组以精确控制蛋白质活性的机制。在细菌中，中央代谢酶和调节蛋白，包括那些与毒力有关的酶，可以作为乙酰化的靶标。在这项研究中，我们直接将霍乱弧菌中可能的乙酰化系统与代谢物依赖的毒力联系起来。我们证明了cobb和yfiQ基因分别编码脱乙酰酶和乙酰转移酶的同源物，调节霍乱弧菌乙酸酯的代谢，乙酸酯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。果蝇是霍乱弧菌感染的节肢动物模型宿主，在果蝇体内，病原体在胃肠道内消耗醋酸盐，从而导致苍蝇死亡。我们发现Cobb基因的缺失阻碍了在醋酸盐最低限度的培养基上的生长，推迟了富含醋酸盐培养基中醋酸盐的消耗，并降低了霍乱弧菌对果蝇的毒力。这些影响可以通过补充Cobb或在ΔCobb背景中引入yfiq的删除来逆转。我们进一步表明，Cobb控制着甘油三酯在果蝇中肠中的积累，这表明Cobb直接调节体内的代谢物水平。在大肠杆菌K-12中，yfiQ被cAMP-cAMP受体蛋白(CRP)上调，我们在霍乱弧菌中发现了类似的调节模式，认为该系统是在类似的环境提示下被激活的。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和它们定植的宿主之间的代谢物交换来调节感染的结果。重要性霍乱弧菌在人类中会导致严重的疾病，而且菌株可以在与多种宿主物种相关的环境中存活。通过研究这些相互作用的分子机制，我们可以更好地了解影响这种全球病原体的生态和进化的制约因素。感染霍乱弧菌的果蝇模型表明，苍蝇胃肠道内醋酸盐和其他小代谢物的细菌调节对其毒力至关重要。在这里，我们证明了可能改变霍乱弧菌蛋白质组的基因影响对果蝇的毒力，最有可能的是通过调节控制醋酸盐和其他小分子消耗的中心代谢途径。这些发现进一步突显了调节细菌新陈代谢的多个层面，以改变细菌与宿主之间的相互作用轨迹。
The bacterium Vibrio cholerae 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 Drosophila model of Vibrio cholerae 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 V. cholerae affect virulence toward Drosophila, 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. ABSTRACT 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 Vibrio cholerae. We demonstrate that the cobB and yfiQ genes, which encode homologs of a deacetylase and an acetyltransferase, respectively, modulate V. cholerae metabolism of acetate, a bacterially derived short-chain fatty acid with important physiological roles in a diversity of host organisms. In Drosophila melanogaster, a model arthropod host for V. cholerae infection, the pathogen consumes acetate within the gastrointestinal tract, which contributes to fly mortality. We show that deletion of cobB impairs growth on acetate minimal medium, delays the consumption of acetate from rich medium, and reduces virulence of V. cholerae toward Drosophila. These impacts can be reversed by complementing cobB or by introducing a deletion of yfiQ into the ΔcobB background. We further show that cobB controls the accumulation of triglycerides in the Drosophila midgut, which suggests that cobB directly modulates metabolite levels in vivo. In Escherichia coli K-12, yfiQ is upregulated by cAMP-cAMP receptor protein (CRP), and we identified a similar pattern of regulation in V. cholerae, 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. IMPORTANCE The bacterium Vibrio cholerae 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 Drosophila model of Vibrio cholerae 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 V. cholerae affect virulence toward Drosophila, 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.