Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility

ABSTRACT Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFN-γ)-inducible host defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol, but the antimicrobial function of...

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Autores principales:	Anthony S. Piro, Dulcemaria Hernandez, Sarah Luoma, Eric M. Feeley, Ryan Finethy, Azeb Yirga, Eva M. Frickel, Cammie F. Lesser, Jörn Coers
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Burkholderia E3 ligase IpaH9.8 LPS O antigen Shigella Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/51771ab8e9bf43aaa2843d2a7d4c7174
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spelling	oai:doaj.org-article:51771ab8e9bf43aaa2843d2a7d4c71742021-11-15T15:51:55ZDetection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility10.1128/mBio.01979-172150-7511https://doaj.org/article/51771ab8e9bf43aaa2843d2a7d4c71742017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01979-17https://doaj.org/toc/2150-7511ABSTRACT Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFN-γ)-inducible host defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol, but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique among the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram-negative bacteria, Burkholderia thailandensis and Shigella flexneri. Rough lipopolysaccharide (LPS) mutants of S. flexneri colocalize with GBP1 less frequently than wild-type S. flexneri does, suggesting that host recognition of O antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C terminus, promotes the corecruitment of four additional GBP paralogs (GBP2, GBP3, GBP4, and GBP6). GBP1-decorated Shigella organisms replicate but fail to form actin tails, leading to their intracellular aggregation. Consequentially, the wild type but not the triple-arginine GBP1 mutant restricts S. flexneri cell-to-cell spread. Furthermore, human-adapted S. flexneri, through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non-human-adapted bacillus B. thailandensis. These studies reveal that human GBP1 uniquely functions as an intracellular “glue trap,” inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human defense program, S. flexneri has evolved an effective counterdefense to restrict GBP1 recruitment. IMPORTANCE Several pathogenic bacterial species evolved to invade, reside in, and replicate inside the cytosol of their host cells. One adaptation common to most cytosolic bacterial pathogens is the ability to coopt the host’s actin polymerization machinery in order to generate force for intracellular movement. This actin-based motility enables Gram-negative bacteria, such as Shigella species, to propel themselves into neighboring cells, thereby spreading from host cell to host cell without exiting the intracellular environment. Here, we show that the human protein GBP1 acts as a cytosolic “glue trap,” capturing cytosolic Gram-negative bacteria through a unique protein motif and preventing disseminated infections in cell culture models. To escape from this GBP1-mediated host defense, Shigella employs a virulence factor that prevents or dislodges the association of GBP1 with cytosolic bacteria. Thus, therapeutic strategies to restore GBP1 binding to Shigella may lead to novel treatment options for shigellosis in the future.Anthony S. PiroDulcemaria HernandezSarah LuomaEric M. FeeleyRyan FinethyAzeb YirgaEva M. FrickelCammie F. LesserJörn CoersAmerican Society for MicrobiologyarticleBurkholderiaE3 ligaseIpaH9.8LPSO antigenShigellaMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Burkholderia E3 ligase IpaH9.8 LPS O antigen Shigella Microbiology QR1-502
spellingShingle	Burkholderia E3 ligase IpaH9.8 LPS O antigen Shigella Microbiology QR1-502 Anthony S. Piro Dulcemaria Hernandez Sarah Luoma Eric M. Feeley Ryan Finethy Azeb Yirga Eva M. Frickel Cammie F. Lesser Jörn Coers Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility
description	ABSTRACT Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFN-γ)-inducible host defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol, but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique among the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram-negative bacteria, Burkholderia thailandensis and Shigella flexneri. Rough lipopolysaccharide (LPS) mutants of S. flexneri colocalize with GBP1 less frequently than wild-type S. flexneri does, suggesting that host recognition of O antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C terminus, promotes the corecruitment of four additional GBP paralogs (GBP2, GBP3, GBP4, and GBP6). GBP1-decorated Shigella organisms replicate but fail to form actin tails, leading to their intracellular aggregation. Consequentially, the wild type but not the triple-arginine GBP1 mutant restricts S. flexneri cell-to-cell spread. Furthermore, human-adapted S. flexneri, through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non-human-adapted bacillus B. thailandensis. These studies reveal that human GBP1 uniquely functions as an intracellular “glue trap,” inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human defense program, S. flexneri has evolved an effective counterdefense to restrict GBP1 recruitment. IMPORTANCE Several pathogenic bacterial species evolved to invade, reside in, and replicate inside the cytosol of their host cells. One adaptation common to most cytosolic bacterial pathogens is the ability to coopt the host’s actin polymerization machinery in order to generate force for intracellular movement. This actin-based motility enables Gram-negative bacteria, such as Shigella species, to propel themselves into neighboring cells, thereby spreading from host cell to host cell without exiting the intracellular environment. Here, we show that the human protein GBP1 acts as a cytosolic “glue trap,” capturing cytosolic Gram-negative bacteria through a unique protein motif and preventing disseminated infections in cell culture models. To escape from this GBP1-mediated host defense, Shigella employs a virulence factor that prevents or dislodges the association of GBP1 with cytosolic bacteria. Thus, therapeutic strategies to restore GBP1 binding to Shigella may lead to novel treatment options for shigellosis in the future.
format	article
author	Anthony S. Piro Dulcemaria Hernandez Sarah Luoma Eric M. Feeley Ryan Finethy Azeb Yirga Eva M. Frickel Cammie F. Lesser Jörn Coers
author_facet	Anthony S. Piro Dulcemaria Hernandez Sarah Luoma Eric M. Feeley Ryan Finethy Azeb Yirga Eva M. Frickel Cammie F. Lesser Jörn Coers
author_sort	Anthony S. Piro
title	Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility
title_short	Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility
title_full	Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility
title_fullStr	Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility
title_full_unstemmed	Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility
title_sort	detection of cytosolic <italic toggle="yes">shigella flexneri</italic> via a c-terminal triple-arginine motif of gbp1 inhibits actin-based motility
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/51771ab8e9bf43aaa2843d2a7d4c7174
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Detection of Cytosolic <italic toggle="yes">Shigella flexneri</italic> via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility

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