Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP

ABSTRACT Bacteria can utilize alternative σ factors to regulate sets of genes in response to changes in the environment. The largest and most diverse group of alternative σ factors are the extracytoplasmic function (ECF) σ factors. σP is an ECF σ factor found in Bacillus anthracis, Bacillus cereus,...

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Autores principales:	Theresa D. Ho, Kelsie M. Nauta, Ute Müh, Craig D. Ellermeier
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	cell envelope extracellular signaling gene expression sigma factors signal transduction stress response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c53f3ef25ee6481ebcfeee9be7cbd809
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spelling	oai:doaj.org-article:c53f3ef25ee6481ebcfeee9be7cbd8092021-11-15T15:22:27ZActivation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP10.1128/mSphere.00511-192379-5042https://doaj.org/article/c53f3ef25ee6481ebcfeee9be7cbd8092019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00511-19https://doaj.org/toc/2379-5042ABSTRACT Bacteria can utilize alternative σ factors to regulate sets of genes in response to changes in the environment. The largest and most diverse group of alternative σ factors are the extracytoplasmic function (ECF) σ factors. σP is an ECF σ factor found in Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis. Previous work showed that σP is induced by ampicillin, a β-lactam antibiotic, and required for resistance to ampicillin. However, it was not known how activation of σP is controlled or what other antibiotics may activate σP. Here, we report that activation of σP is specific to a subset of β-lactams and that σP is required for resistance to these β-lactams. We demonstrate that activation of σP is controlled by the proteolytic destruction of the anti-σ factor RsiP and that degradation of RsiP requires multiple proteases. Upon exposure to β-lactams, the extracellular domain of RsiP is cleaved by an unknown protease, which we predict cleaves at site-1. Following cleavage by the unknown protease, the N terminus of RsiP is further degraded by the site-2 intramembrane protease RasP. Our data indicate that RasP cleavage of RsiP is not the rate-limiting step in σP activation. This proteolytic cascade leads to activation of σP, which induces resistance to β-lactams likely via increased expression of β-lactamases. IMPORTANCE The discovery of antibiotics to treat bacterial infections has had a dramatic and positive impact on human health. However, shortly after the introduction of a new antibiotic, bacteria often develop resistance. The bacterial cell envelope is essential for cell viability and is the target of many of the most commonly used antibiotics, including β-lactam antibiotics. Resistance to β-lactams is often dependent upon β-lactamases. In B. cereus, B. thuringiensis, and some B. anthracis strains, the expression of some β-lactamases is inducible. This inducible β-lactamase expression is controlled by activation of an alternative σ factor called σP. Here, we show that β-lactam antibiotics induce σP activation by degradation of the anti-σ factor RsiP.Theresa D. HoKelsie M. NautaUte MühCraig D. EllermeierAmerican Society for Microbiologyarticlecell envelopeextracellular signalinggene expressionsigma factorssignal transductionstress responseMicrobiologyQR1-502ENmSphere, Vol 4, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	cell envelope extracellular signaling gene expression sigma factors signal transduction stress response Microbiology QR1-502
spellingShingle	cell envelope extracellular signaling gene expression sigma factors signal transduction stress response Microbiology QR1-502 Theresa D. Ho Kelsie M. Nauta Ute Müh Craig D. Ellermeier Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP
description	ABSTRACT Bacteria can utilize alternative σ factors to regulate sets of genes in response to changes in the environment. The largest and most diverse group of alternative σ factors are the extracytoplasmic function (ECF) σ factors. σP is an ECF σ factor found in Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis. Previous work showed that σP is induced by ampicillin, a β-lactam antibiotic, and required for resistance to ampicillin. However, it was not known how activation of σP is controlled or what other antibiotics may activate σP. Here, we report that activation of σP is specific to a subset of β-lactams and that σP is required for resistance to these β-lactams. We demonstrate that activation of σP is controlled by the proteolytic destruction of the anti-σ factor RsiP and that degradation of RsiP requires multiple proteases. Upon exposure to β-lactams, the extracellular domain of RsiP is cleaved by an unknown protease, which we predict cleaves at site-1. Following cleavage by the unknown protease, the N terminus of RsiP is further degraded by the site-2 intramembrane protease RasP. Our data indicate that RasP cleavage of RsiP is not the rate-limiting step in σP activation. This proteolytic cascade leads to activation of σP, which induces resistance to β-lactams likely via increased expression of β-lactamases. IMPORTANCE The discovery of antibiotics to treat bacterial infections has had a dramatic and positive impact on human health. However, shortly after the introduction of a new antibiotic, bacteria often develop resistance. The bacterial cell envelope is essential for cell viability and is the target of many of the most commonly used antibiotics, including β-lactam antibiotics. Resistance to β-lactams is often dependent upon β-lactamases. In B. cereus, B. thuringiensis, and some B. anthracis strains, the expression of some β-lactamases is inducible. This inducible β-lactamase expression is controlled by activation of an alternative σ factor called σP. Here, we show that β-lactam antibiotics induce σP activation by degradation of the anti-σ factor RsiP.
format	article
author	Theresa D. Ho Kelsie M. Nauta Ute Müh Craig D. Ellermeier
author_facet	Theresa D. Ho Kelsie M. Nauta Ute Müh Craig D. Ellermeier
author_sort	Theresa D. Ho
title	Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP
title_short	Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP
title_full	Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP
title_fullStr	Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP
title_full_unstemmed	Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP
title_sort	activation of the extracytoplasmic function σ factor σ<sup>p</sup> by β-lactams in <named-content content-type="genus-species">bacillus thuringiensis</named-content> requires the site-2 protease rasp
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/c53f3ef25ee6481ebcfeee9be7cbd809
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Activation of the Extracytoplasmic Function σ Factor σ<sup>P</sup> by β-Lactams in <named-content content-type="genus-species">Bacillus thuringiensis</named-content> Requires the Site-2 Protease RasP

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