A central role for carbon-overflow pathways in the modulation of bacterial cell death.
A central role for carbon-overflow pathways in the modulation of bacterial cell death.
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DOI：
10.1371/journal.ppat.1004205
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发表时间：
2014-06
期刊：
影响因子：
6.7
通讯作者：
Bayles KW
中科院分区：
文献类型：
--
作者：
Thomas VC;Sadykov MR;Chaudhari SS;Jones J;Endres JL;Widhelm TJ;Ahn JS;Jawa RS;Zimmerman MC;Bayles KW
与真核生物的发育程序类似，细胞亚群的死亡被认为有利于细菌生物膜的发育。然而，介导细胞死亡的严格控制的机制在群体水平上并不清楚。在这里，我们揭示了CidR依赖性丙酮酸氧化酶（CidC）和α-乙酰乳酸合成酶/脱羧酶（AlsSD）溢出代谢途径，这是活跃在葡萄球菌生物膜的发展，调节细胞死亡，以实现最佳的生物膜生物量。而源自CidC活性的乙酸盐通过依赖于细胞内酸化和呼吸抑制的机制增强细胞中的细胞死亡，AlsSD活性通过将碳通量转向中性而不是酸性副产物并在该过程中消耗细胞内质子来有效地对抗CidC作用。此外，伴随细胞死亡的代谢活化的生理特征与真核细胞程序性细胞死亡的标志具有显著的相似性，包括活性氧簇的产生和DNA损伤。最后，我们证明了细胞死亡的代谢调节不仅影响生物膜的发育，而且影响生物膜依赖性疾病的结局。鉴于这种碳溢出途径在不同细菌物种中的普遍存在，我们认为细胞死亡的代谢控制可能是原核生物发育的一个基本特征。包括病原体金黄色葡萄球菌在内的许多细菌物种能够粘附在表面并形成称为生物膜的复杂群落。从感染控制的角度来看，这种生长模式可能特别具有挑战性，因为它们通常对抗生素和宿主免疫系统具有抗性。虽然生物膜形成的发育过程还不完全清楚，但最近的证据表明，亚群的细胞死亡对其成熟至关重要。在这项研究中，我们提供了关于控制细胞死亡的代谢途径的见解，并证明了乙酸盐，葡萄糖代谢酶的副产物，加强了一种形式的细胞死亡，表现出在真核生物中细胞凋亡的生理和生化标志。最后，我们证明了改变代谢途径的能力，调节乙酸介导的细胞死亡在S。金黄色葡萄球菌影响生物膜相关疾病如感染性心内膜炎的结果。
Similar to developmental programs in eukaryotes, the death of a subpopulation of cells is thought to benefit bacterial biofilm development. However mechanisms that mediate a tight control over cell death are not clearly understood at the population level. Here we reveal that CidR dependent pyruvate oxidase (CidC) and α-acetolactate synthase/decarboxylase (AlsSD) overflow metabolic pathways, which are active during staphylococcal biofilm development, modulate cell death to achieve optimal biofilm biomass. Whereas acetate derived from CidC activity potentiates cell death in cells by a mechanism dependent on intracellular acidification and respiratory inhibition, AlsSD activity effectively counters CidC action by diverting carbon flux towards neutral rather than acidic byproducts and consuming intracellular protons in the process. Furthermore, the physiological features that accompany metabolic activation of cell death bears remarkable similarities to hallmarks of eukaryotic programmed cell death, including the generation of reactive oxygen species and DNA damage. Finally, we demonstrate that the metabolic modulation of cell death not only affects biofilm development but also biofilm-dependent disease outcomes. Given the ubiquity of such carbon overflow pathways in diverse bacterial species, we propose that the metabolic control of cell death may be a fundamental feature of prokaryotic development. Many bacterial species including the pathogen Staphylococcus aureus are capable of adhering to surfaces and forming complex communities called biofilms. This mode of growth can be particularly challenging from an infection control standpoint, as they are often refractory to antibiotics and host immune system. Although developmental processes underlying biofilm formation are not entirely clear, recent evidence suggests that cell death of a subpopulation is crucial for its maturation. In this study we provide insight regarding the metabolic pathways that control cell death and demonstrate that acetate, a by-product of glucose catabolism, potentiates a form of cell death that exhibits physiological and biochemical hallmarks of apoptosis in eukaryotic organisms. Finally, we demonstrate that altering the ability of metabolic pathways that regulate acetate mediated cell death in S. aureus affects the outcome of biofilm-related diseases, such as infective endocarditis.
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影响因子：
16
作者：
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