A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>

ABSTRACT A multifunctional autoprocessing repeats-in-toxin (MARTX) toxin plays an essential role in the virulence of many pathogens, including a fulminating human pathogen Vibrio vulnificus. H-NS and HlyU repress and derepress expression of the MARTX toxin gene rtxA in V. vulnificus, respectively. H...

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Autores principales:	Zee-Won Lee, Seung-Ho Hwang, Garam Choi, Kyung Ku Jang, Tae Hee Lee, Kyung Min Chung, Byoung Sik Kim, Sang Ho Choi
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	host environmental signals MARTX toxin regulatory network Vibrio vulnificus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1f3e685fd2ae4bfd9e026528cf137726
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spelling	oai:doaj.org-article:1f3e685fd2ae4bfd9e026528cf1377262021-11-15T15:56:44ZA MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>10.1128/mBio.00723-202150-7511https://doaj.org/article/1f3e685fd2ae4bfd9e026528cf1377262020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00723-20https://doaj.org/toc/2150-7511ABSTRACT A multifunctional autoprocessing repeats-in-toxin (MARTX) toxin plays an essential role in the virulence of many pathogens, including a fulminating human pathogen Vibrio vulnificus. H-NS and HlyU repress and derepress expression of the MARTX toxin gene rtxA in V. vulnificus, respectively. However, little is known about other regulatory proteins and environmental signals involved in rtxA regulation. In this study, we found that a leucine-responsive regulatory protein (Lrp) activates rtxA by binding directly and specifically to the rtxA promoter, PrtxA. Phased hypersensitivity resulting from DNase I cleavage of the PrtxA regulatory region suggests that Lrp probably induces DNA bending in PrtxA. Lrp activates PrtxA independently of H-NS and HlyU, and leucine inhibits Lrp binding to PrtxA and reduces the Lrp-mediated activation. Furthermore, a cyclic AMP receptor protein (CRP) represses PrtxA, and exogenous glucose relieves the CRP-mediated repression. Biochemical and mutational analyses demonstrated that CRP binds directly and specifically to the upstream region of PrtxA, which presumably alters the DNA conformation in PrtxA and thus represses rtxA. Moreover, CRP represses expression of lrp and hlyU by binding directly to their upstream regions, forming coherent feed-forward loops with Lrp and HlyU. In conclusion, expression of rtxA is controlled by a regulatory network comprising CRP, Lrp, H-NS, and HlyU in response to changes in host environmental signals such as leucine and glucose. This collaborative regulation enables the elaborate expression of rtxA, thereby enhancing the fitness and pathogenesis of V. vulnificus during the course of infection. IMPORTANCE A MARTX toxin, RtxA, is an essential virulence factor of many pathogens, including Vibrio species. H-NS and HlyU repress and derepress, respectively, rtxA expression of a life-threatening pathogen, Vibrio vulnificus. We found that Lrp directly activates rtxA independently of H-NS and HlyU, and leucine inhibits the Lrp-mediated activation of rtxA. Furthermore, we demonstrated that CRP represses rtxA but derepresses in the presence of exogenous glucose. CRP represses rtxA not only directly by binding to upstream of rtxA but also indirectly by repressing lrp and hlyU. This is the first report of a regulatory network comprising CRP, Lrp, H-NS, and HlyU, which coordinates the rtxA expression in response to environmental signals such as leucine and glucose during infection. This elaborate regulatory network will enhance the fitness of V. vulnificus and contribute to its successful infection within the host.Zee-Won LeeSeung-Ho HwangGaram ChoiKyung Ku JangTae Hee LeeKyung Min ChungByoung Sik KimSang Ho ChoiAmerican Society for Microbiologyarticlehost environmental signalsMARTX toxinregulatory networkVibrio vulnificusMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	host environmental signals MARTX toxin regulatory network Vibrio vulnificus Microbiology QR1-502
spellingShingle	host environmental signals MARTX toxin regulatory network Vibrio vulnificus Microbiology QR1-502 Zee-Won Lee Seung-Ho Hwang Garam Choi Kyung Ku Jang Tae Hee Lee Kyung Min Chung Byoung Sik Kim Sang Ho Choi A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>
description	ABSTRACT A multifunctional autoprocessing repeats-in-toxin (MARTX) toxin plays an essential role in the virulence of many pathogens, including a fulminating human pathogen Vibrio vulnificus. H-NS and HlyU repress and derepress expression of the MARTX toxin gene rtxA in V. vulnificus, respectively. However, little is known about other regulatory proteins and environmental signals involved in rtxA regulation. In this study, we found that a leucine-responsive regulatory protein (Lrp) activates rtxA by binding directly and specifically to the rtxA promoter, PrtxA. Phased hypersensitivity resulting from DNase I cleavage of the PrtxA regulatory region suggests that Lrp probably induces DNA bending in PrtxA. Lrp activates PrtxA independently of H-NS and HlyU, and leucine inhibits Lrp binding to PrtxA and reduces the Lrp-mediated activation. Furthermore, a cyclic AMP receptor protein (CRP) represses PrtxA, and exogenous glucose relieves the CRP-mediated repression. Biochemical and mutational analyses demonstrated that CRP binds directly and specifically to the upstream region of PrtxA, which presumably alters the DNA conformation in PrtxA and thus represses rtxA. Moreover, CRP represses expression of lrp and hlyU by binding directly to their upstream regions, forming coherent feed-forward loops with Lrp and HlyU. In conclusion, expression of rtxA is controlled by a regulatory network comprising CRP, Lrp, H-NS, and HlyU in response to changes in host environmental signals such as leucine and glucose. This collaborative regulation enables the elaborate expression of rtxA, thereby enhancing the fitness and pathogenesis of V. vulnificus during the course of infection. IMPORTANCE A MARTX toxin, RtxA, is an essential virulence factor of many pathogens, including Vibrio species. H-NS and HlyU repress and derepress, respectively, rtxA expression of a life-threatening pathogen, Vibrio vulnificus. We found that Lrp directly activates rtxA independently of H-NS and HlyU, and leucine inhibits the Lrp-mediated activation of rtxA. Furthermore, we demonstrated that CRP represses rtxA but derepresses in the presence of exogenous glucose. CRP represses rtxA not only directly by binding to upstream of rtxA but also indirectly by repressing lrp and hlyU. This is the first report of a regulatory network comprising CRP, Lrp, H-NS, and HlyU, which coordinates the rtxA expression in response to environmental signals such as leucine and glucose during infection. This elaborate regulatory network will enhance the fitness of V. vulnificus and contribute to its successful infection within the host.
format	article
author	Zee-Won Lee Seung-Ho Hwang Garam Choi Kyung Ku Jang Tae Hee Lee Kyung Min Chung Byoung Sik Kim Sang Ho Choi
author_facet	Zee-Won Lee Seung-Ho Hwang Garam Choi Kyung Ku Jang Tae Hee Lee Kyung Min Chung Byoung Sik Kim Sang Ho Choi
author_sort	Zee-Won Lee
title	A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>
title_short	A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>
title_full	A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>
title_fullStr	A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>
title_full_unstemmed	A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>
title_sort	martx toxin <italic toggle="yes">rtxa</italic> gene is controlled by host environmental signals through a crp-coordinated regulatory network in <named-content content-type="genus-species">vibrio vulnificus</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/1f3e685fd2ae4bfd9e026528cf137726
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A MARTX Toxin <italic toggle="yes">rtxA</italic> Gene Is Controlled by Host Environmental Signals through a CRP-Coordinated Regulatory Network in <named-content content-type="genus-species">Vibrio vulnificus</named-content>

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