Understanding the Streptococcus mutans Cid/Lrg System through CidB Function
Understanding the Streptococcus mutans Cid/Lrg System through CidB Function
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DOI：
10.1128/aem.01499-16
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发表时间：
2016-10-01
影响因子：
4.4
通讯作者：
Rice, Kelly C.
中科院分区：
文献类型：
--
作者：
Ahn, Sang-Joon;Rice, Kelly C.
变形链球菌lrgAB和cidAB操纵子先前被描述为一个潜在的模型系统，以剖析变形链球菌生物膜发育的复杂性和毒力。在此，我们试图通过聚焦CidB进一步表征Cid/Lrg系统，CidB已被证明对变形链球菌在非首选富氧条件下生存和持续的能力至关重要。我们发现cidB的表达水平对S. mutans的氧化应激耐受性至关重要，很可能是通过影响lrg的表达。有趣的是，cidB突变体的有氧生长表型受损可以通过CidA或LrgA的额外损失来恢复。cid和lrg的生长依赖性表达被证明受到CcpA和VicKR双组分系统（TCS）的严格控制，这两种调节因子分别在控制主要分解代谢途径和细胞包膜稳态中起重要作用。RNA测序（RNA- seq）分析显示，cidB突变导致了全球基因表达的变化，包括中枢代谢和毒力过程的主要结构域，特别是与氧化应激抵抗有关的结构域。CidB的缺失也显著改变了基因组岛（GI） TnSmu1和TnSmu2、CRISPR（聚集规律间隔短回语重复序列）-Cas系统和毒素-抗毒素（T/A）模块相关基因的表达。综上所述，这些数据表明CidB影响了变形链球菌的应激反应以及基本的细胞生理学，并进一步表明Cid/ lrg介导的细胞过程、变形链球菌的致病性以及可能的程序性生长停滞和细胞死亡机制之间存在潜在的联系。变形链球菌在各种有害或应激条件下生存的能力，以及作为稳定的口腔生物膜群落的重要成员的能力，是其持久性和致癌性的重要因素。在本研究中，同源的cidAB和lrgAB操作子通过对CidB的功能和转录组学分析进一步表征，在之前的研究中，cidAB和lrgAB操作子在S. mutans有氧生长过程中被认为是高度平衡和协调的。精确控制CidB水平可影响lrg的表达、氧化应激耐受性、主要代谢结构域以及与细胞死亡和裂解相关的分子模块。这项研究促进了我们对Cid/Lrg系统作为复杂环境信号（如氧化应激）整合到调节变形链球菌毒力和细胞稳态的调节网络中的关键角色的理解。
The Streptococcus mutans lrgAB and cidAB operons have been previously described as a potential model system to dissect the complexity of biofilm development and virulence of S. mutans. Herein, we have attempted to further characterize the Cid/Lrg system by focusing on CidB, which has been shown to be critical for the ability of S. mutans to survive and persist in a nonpreferred oxygen-enriched condition. We have found that the expression level of cidB is critical to oxidative stress tolerance of S. mutans, most likely by impacting lrg expression. Intriguingly, the impaired aerobic growth phenotype of the cidB mutant could be restored by the additional loss of either CidA or LrgA. Growth-dependent expression of cid and lrg was demonstrated to be tightly under the control of both CcpA and the VicKR two-component system (TCS), regulators known to play an essential role in controlling major catabolic pathways and cell envelope homeostasis, respectively. RNA sequencing (RNA-Seq) analysis revealed that mutation of cidB resulted in global gene expression changes, comprising major domains of central metabolism and virulence processes, particularly in those involved with oxidative stress resistance. Loss of CidB also significantly changed the expression of genes related to genomic islands (GI) TnSmu1 and TnSmu2, the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas system, and toxin-antitoxin (T/A) modules. Taken together, these data show that CidB impinges on the stress response, as well as the fundamental cellular physiology of S. mutans, and further suggest a potential link between Cid/Lrg-mediated cellular processes, S. mutans pathogenicity, and possible programmed growth arrest and cell death mechanisms.IMPORTANCEThe ability of Streptococcus mutans to survive a variety of harmful or stressful conditions and to emerge as a numerically significant member of stable oral biofilm communities are essential elements for its persistence and cariogenicity. In this study, the homologous cidAB and lrgAB operons, previously identified as being highly balanced and coordinated during S. mutans aerobic growth, were further characterized through the functional and transcriptomic analysis of CidB. Precise control of CidB levels is shown to impact the expression of lrg, oxidative stress tolerance, major metabolic domains, and the molecular modules linked to cell death and lysis. This study advances our understanding of the Cid/Lrg system as a key player in the integration of complex environmental signals (such as oxidative stress) into the regulatory networks that modulate S. mutans virulence and cell homeostasis.