Two group A streptococcal peptide pheromones act through opposing Rgg regulators to control biofilm development.
Two group A streptococcal peptide pheromones act through opposing Rgg regulators to control biofilm development.
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DOI：
10.1371/journal.ppat.1002190
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发表时间：
2011-08
期刊：
影响因子：
6.7
通讯作者：
Federle MJ
中科院分区：
文献类型：
--
作者：
Chang JC;LaSarre B;Jimenez JC;Aggarwal C;Federle MJ
化脓性链球菌（Streptococcus pyogenes，GAS）是一种重要的人类病原体，偶尔引起局部感染，很少引起严重的侵袭性疾病，死亡率高。GAS如何调节用于定殖宿主和避免免疫反应的因子的表达仍然知之甚少。细胞间通讯是细菌协调基因表达以抵御宿主攻击和竞争细菌的重要手段，但在GAS中尚未阐明保守的细胞间信号传导系统。在GAS基因组内编码有四个rgg样基因，其中两个（rgg 2和rgg 3）没有先前描述的功能。我们测试了rgg2或rgg3依赖于细胞外肽来控制靶基因调控的假设。我们发现，Rgg2和Rgg3一起紧密调控两个连锁的基因编码新的肽信息素。Rgg2激活转录的信息素基因的充分诱导所需的，而Rgg3起着拮抗作用，抑制信息素的表达。被称为SHP2和SHP3的活性信息素信号是短的和疏水的（DI [I/L] IIVGG），并且，尽管在序列上高度相似，但观察到它们破坏Rgg3-DNA复合物的能力是不同的，这表明启动子的特异性和差异激活是Rgg2/3调节回路的特征。SHP-信息素信号传导需要完整的寡肽通透酶（opp）和金属蛋白酶（eep），支持前肽被分泌、加工成成熟形式并随后输入细胞质以直接与Rgg受体相互作用的模型。Rgg2/3途径的信息素刺激的至少一个结果是生物膜的生物发生增加，其抵消RopB（Rgg1）对生物膜的负调节。这些数据提供了第一个证明，Rgg依赖的群体感应功能在气体和证实的作用，Rggs发挥肽受体在厚壁菌门。A组链球菌（GAS，化脓性链球菌）是引起包括咽炎和中毒性休克在内的多种疾病的病原体，但也通常无症状地在人群中携带。是什么导致了携带者和致病状态之间的转换仍然知之甚少。细菌中的细胞间信号传导，也称为群体感应，是许多病原体中毒力基因调控的重要机制，但在GAS中尚未阐明保守的群体感应途径。在这里，我们确定和表征一个新的气体群体感应电路，由两个调节器，响应两个分泌肽信号。这些调节因子是一类研究很少的蛋白质（称为Rgg）的成员，这些蛋白质在革兰氏阳性细菌中发现。成熟的肽信号，这里称为信息素，因为它们能够引起群体成员的反应，增强生物膜的产生，这与鼻咽定殖，寄生虫治疗失败和坏死感染有关。我们发现，外源性添加合成产生的信息素也诱导生物膜生长，表明GAS行为可以通过人工信号操纵，并提供了替代治疗的可能性。
Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human commensal that occasionally causes localized infections and less frequently causes severe invasive disease with high mortality rates. How GAS regulates expression of factors used to colonize the host and avoid immune responses remains poorly understood. Intercellular communication is an important means by which bacteria coordinate gene expression to defend against host assaults and competing bacteria, yet no conserved cell-to-cell signaling system has been elucidated in GAS. Encoded within the GAS genome are four rgg-like genes, two of which (rgg2 and rgg3) have no previously described function. We tested the hypothesis that rgg2 or rgg3 rely on extracellular peptides to control target-gene regulation. We found that Rgg2 and Rgg3 together tightly regulate two linked genes encoding new peptide pheromones. Rgg2 activates transcription of and is required for full induction of the pheromone genes, while Rgg3 plays an antagonistic role and represses pheromone expression. The active pheromone signals, termed SHP2 and SHP3, are short and hydrophobic (DI[I/L]IIVGG), and, though highly similar in sequence, their ability to disrupt Rgg3-DNA complexes were observed to be different, indicating that specificity and differential activation of promoters are characteristics of the Rgg2/3 regulatory circuit. SHP-pheromone signaling requires an intact oligopeptide permease (opp) and a metalloprotease (eep), supporting the model that pro-peptides are secreted, processed to the mature form, and subsequently imported to the cytoplasm to interact directly with the Rgg receptors. At least one consequence of pheromone stimulation of the Rgg2/3 pathway is increased biogenesis of biofilms, which counteracts negative regulation of biofilms by RopB (Rgg1). These data provide the first demonstration that Rgg-dependent quorum sensing functions in GAS and substantiate the role that Rggs play as peptide receptors across the Firmicute phylum. Group A Streptococcus (GAS, Streptococcus pyogenes) is a pathogen responsible for a wide variety of diseases including pharyngitis and toxic shock, but is also commonly carried in the human population asymptomatically. What causes the switch between carrier and pathogenic states remains poorly understood. Cell-to-cell signaling in bacteria, also known as quorum sensing, is an important mechanism for virulence gene regulation in many pathogens, yet no conserved quorum sensing pathway has been elucidated in GAS. Here we identify and characterize a new GAS quorum-sensing circuit that consists of two regulators that respond to two secreted peptide signals. The regulators are members of a class of generally poorly studied proteins (known as Rgg) found throughout Gram-positive bacteria. The mature peptide signals, here termed pheromones for their ability to elicit responses in members of the population, enhance the production of biofilms, which have been associated with nasopharyngeal colonization, antibiotic-treatment failures, and necrotic infections. We found that exogenous addition of synthetically-produced pheromone also induced biofilm growth, demonstrating that GAS behavior can be manipulated by artificial signals and offering the possibility for alternative therapeutic treatments.
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影响因子：
3.6
作者：
Ansaldi, M;Marolt, D;Dubnau, D
通讯作者：
Dubnau, D
影响因子：
3.1
作者：
Chaussee, MS;Sylva, GL;Musser, JM
通讯作者：
Musser, JM
影响因子：
4.8
作者：
Doeven, MK;Abele, R;Poolman, B
通讯作者：
Poolman, B
影响因子：
9.4
作者：
Conley, J;Olson, ME;Davies, HD
通讯作者：
Davies, HD
DOI：
10.1093/protein/10.6.673
发表时间：
1997-06-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Cserzo, M;Wallin, E;Elofsson, A
通讯作者：
Elofsson, A