Center for Pharmaceutical Biotechnology, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America.
PLoS Pathog. 2011 Aug;7(8):e1002190. doi: 10.1371/journal.ppat.1002190. Epub 2011 Aug 4.
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.
化脓链球菌（A 组链球菌，GAS）是一种重要的人体共生菌，偶尔会引起局部感染，较少情况下会引起严重的侵袭性疾病，死亡率较高。GAS 如何调节用于定植宿主和避免免疫反应的因子表达仍知之甚少。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，但尚未在 GAS 中阐明保守的细胞间信号系统。GAS 基因组中编码了四个 rgg 样基因，其中两个（rgg2 和 rgg3）以前没有描述过功能。我们检验了 rgg2 或 rgg3 是否依赖于细胞外肽来控制靶基因调节的假设。我们发现 rgg2 和 rgg3 共同紧密调节两个编码新肽信息素的连锁基因。Rgg2 激活转录并需要完全诱导信息素基因的表达，而 Rgg3 则发挥拮抗作用并抑制信息素表达。活性信息素信号称为 SHP2 和 SHP3，短而疏水（DI[I/L]IIVGG），尽管序列高度相似，但观察到它们破坏 Rgg3-DNA 复合物的能力不同，表明特异性和差异激活启动子是 Rgg2/3 调节回路的特征。SHP-信息素信号需要完整的寡肽渗透酶（opp）和金属蛋白酶（eep），支持前肽被分泌、加工成成熟形式、随后被导入细胞质并直接与 Rgg 受体相互作用的模型。信息素刺激 Rgg2/3 途径的至少一个后果是生物膜的生物发生增加，这抵消了 RopB（Rgg1）对生物膜的负调节。这些数据首次证明了 Rgg 依赖性群体感应在 GAS 中的作用，并证实了 Rggs 在整个厚壁菌门中作为肽受体的作用。
