ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>

ABSTRACT 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 A Streptococcus (GAS). Using immunofluorescence and immunogold electron microscopy, we discovered that LiaF (a membrane-...

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Autores principales:	Yibin Lin, Misu A. Sanson, Luis Alberto Vega, Brittany Shah, Shrijana Regmi, M. Belen Cubria, Anthony R. Flores
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	ExPortal LiaFSR cell envelope stress group A streptococcus membrane microdomain two-component regulatory systems Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c34ef1a1229d4b718ddfb34aee719b40
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spelling	oai:doaj.org-article:c34ef1a1229d4b718ddfb34aee719b402021-11-15T16:19:08ZExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>10.1128/mBio.01804-202150-7511https://doaj.org/article/c34ef1a1229d4b718ddfb34aee719b402020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01804-20https://doaj.org/toc/2150-7511ABSTRACT 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 A Streptococcus (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. IMPORTANCE Bacterial 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 A Streptococcus (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.Yibin LinMisu A. SansonLuis Alberto VegaBrittany ShahShrijana RegmiM. Belen CubriaAnthony R. FloresAmerican Society for MicrobiologyarticleExPortalLiaFSRcell envelope stressgroup A streptococcusmembrane microdomaintwo-component regulatory systemsMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	ExPortal LiaFSR cell envelope stress group A streptococcus membrane microdomain two-component regulatory systems Microbiology QR1-502
spellingShingle	ExPortal LiaFSR cell envelope stress group A streptococcus membrane microdomain two-component regulatory systems Microbiology QR1-502 Yibin Lin Misu A. Sanson Luis Alberto Vega Brittany Shah Shrijana Regmi M. Belen Cubria Anthony R. Flores ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>
description	ABSTRACT 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 A Streptococcus (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. IMPORTANCE Bacterial 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 A Streptococcus (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.
format	article
author	Yibin Lin Misu A. Sanson Luis Alberto Vega Brittany Shah Shrijana Regmi M. Belen Cubria Anthony R. Flores
author_facet	Yibin Lin Misu A. Sanson Luis Alberto Vega Brittany Shah Shrijana Regmi M. Belen Cubria Anthony R. Flores
author_sort	Yibin Lin
title	ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>
title_short	ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>
title_full	ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>
title_fullStr	ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>
title_full_unstemmed	ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>
title_sort	exportal and the liafsr regulatory system coordinate the response to cell membrane stress in <named-content content-type="genus-species">streptococcus pyogenes</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c34ef1a1229d4b718ddfb34aee719b40
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ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in <named-content content-type="genus-species">Streptococcus pyogenes</named-content>

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