ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in Streptococcus pyogenes.
ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in Streptococcus pyogenes.
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ExPortal 和 LiaFSR 监管系统协调化脓性链球菌对细胞膜应激的反应。
DOI：
10.1128/mbio.01804-20
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发表时间：
2020
期刊：
影响因子：
6.4
通讯作者：
Flores,AnthonyR
中科院分区：
文献类型：
--
作者：
Lin,Yibin;Sanson,MisuA;Vega,LuisAlberto;Shah,Brittany;Regmi,Shrijana;Cubria,MBelen;Flores,AnthonyR
LiaFSR是革兰氏阳性菌中对细胞膜应激反应重要的基因调控系统，但在重要的人类病原体群astreplant（GAS）中研究最少。使用免疫荧光和免疫金电子显微镜，我们发现，LiaF（膜结合阻遏蛋白）和LiaS（传感器激酶）驻留在GAS膜微区（ExPortal）。由抗微生物剂诱导的细胞包膜应激导致ExPortal破坏和LiaFSR系统的激活。其存在导致ExPortal破坏和LiaFSR活化的唯一人抗微生物肽是α-防御素人嗜中性粒细胞肽1（hNP-1）。通过靶向基因缺失消除膜心磷脂导致LiaS与GAS ExPortal共定位的丧失和LiaFSR的激活，而LiaF膜定位不受影响。缺乏LiaF或LiaS的同基因突变体揭示了LiaF在ExPortal完整性中的关键作用。因此，LiaF和LiaS通过不同的机制与GAS ExPortal共定位，进一步支持相互依赖。这些都是第一个数据识别多组分信号系统内的ExPortal，从而提供了新的见解细菌膜内信号在气体，可以作为一个范例革兰氏阳性bacteries.IMPORTANCEBacterial双组分系统的感觉和诱导转录变化响应于环境的压力，包括抗菌剂和人类抗菌肽。由于宿主的防御反应所施加的压力可以作为疾病进展或宿主区室的特定时间阶段的标志物，病原体通常协调调节具有毒力因子表达的压力反应程序。细菌识别这些压力并随后诱导转录反应的机制仍然没有很好地理解。在这项研究中，我们表明，LiaFSR通过LiaF和LiaS与AStreatment（GAS）ExPortal组的共定位来感知细胞包膜应激，并直接响应于抗微生物剂或人抗微生物肽对ExPortal的破坏而被激活。我们的研究揭示了革兰氏阳性菌细胞包膜应激的传感，并可能有助于开发针对这些过程的治疗方法。
LiaFSR is a gene regulatory system important for response to cell membrane stress in Gram-positive bacteria but is minimally studied in the important human pathogen group AStreptococcus(GAS). Using immunofluorescence and immunogold electron microscopy, we discovered that LiaF (a membrane-bound repressor protein) and LiaS (a sensor kinase) reside within the GAS membrane microdomain (ExPortal). Cell envelope stress induced by antimicrobials resulted in ExPortal disruption and activation of the LiaFSR system. The only human antimicrobial peptide whose presence resulted in ExPortal disruption and LiaFSR activation was the alpha-defensin human neutrophil peptide 1 (hNP-1). Elimination of membrane cardiolipin through targeted gene deletion resulted in loss of LiaS colocalization with the GAS ExPortal and activation of LiaFSR, whereas LiaF membrane localization was unaffected. Isogenic mutants lacking either LiaF or LiaS revealed a critical role of LiaF in ExPortal integrity. Thus, LiaF and LiaS colocalize with the GAS ExPortal by distinct mechanisms, further supporting codependence. These are the first data identifying a multicomponent signal system within the ExPortal, thereby providing new insight into bacterial intramembrane signaling in GAS that may serve as a paradigm for Gram-positive bacteria.IMPORTANCEBacterial two-component systems sense and induce transcriptional changes in response to environmental stressors, including antimicrobials and human antimicrobial peptides. Since the stresses imposed by the host’s defensive responses may act as markers of specific temporal stages of disease progression or host compartments, pathogens often coordinately regulate stress response programs with virulence factor expression. The mechanism by which bacteria recognize these stresses and subsequently induce transcriptional responses remains not well understood. In this study, we showed that LiaFSR senses cell envelope stress through colocalization of LiaF and LiaS with the group AStreptococcus(GAS) ExPortal and is activated in direct response to ExPortal disruption by antimicrobials or human antimicrobial peptides. Our studies shed new light on the sensing of cell envelope stress in Gram-positive bacteria and may contribute to the development of therapies targeting these processes.