Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

ABSTRACT A primary function of the extracellular proteases of Staphylococcus aureus is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity to influence the accumulation,...

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Autores principales:	Brittney D. Gimza, Maria I. Larias, Bridget G. Budny, Lindsey N. Shaw
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Staphylococcus aureus gene regulation proteases transcriptional regulation virulence factors Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e61be0592ddc48dc8fd0ba1827a35c1e
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spelling	oai:doaj.org-article:e61be0592ddc48dc8fd0ba1827a35c1e2021-11-15T15:27:32ZMapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>10.1128/mSphere.00676-192379-5042https://doaj.org/article/e61be0592ddc48dc8fd0ba1827a35c1e2019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00676-19https://doaj.org/toc/2379-5042ABSTRACT A primary function of the extracellular proteases of Staphylococcus aureus is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity to influence the accumulation, or lack thereof, of individual virulence factors. Herein, we comprehensively map this system, exploring the regulation of the four protease loci by known and novel factors. In so doing, we determined that seven major elements (SarS, SarR, Rot, MgrA, CodY, SaeR, and SarA) form the primary network of control, with the latter three being the most powerful. We note that expression of aureolysin is largely repressed by these factors, while the spl operon is subject to the strongest upregulation of any protease loci, particularly by SarR and SaeR. Furthermore, when exploring scpA expression, we find it to be profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). We also present the screening of >100 regulator mutants of S. aureus, identifying 7 additional factors (ArgR2, AtlR, MntR, Rex, XdrA, Rbf, and SarU) that form a secondary circuit of protease control. Primarily, these elements serve as activators, although we reveal XdrA as a new repressor of protease expression. With the exception or ArgR2, each of the new effectors appears to work through the primary network of regulation to influence protease production. Collectively, we present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation and suggest that its existence speaks to the importance of these enzymes to S. aureus physiology and pathogenic potential. IMPORTANCE The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in Staphylococcus aureus.Brittney D. GimzaMaria I. LariasBridget G. BudnyLindsey N. ShawAmerican Society for MicrobiologyarticleStaphylococcus aureusgene regulationproteasestranscriptional regulationvirulence factorsMicrobiologyQR1-502ENmSphere, Vol 4, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus gene regulation proteases transcriptional regulation virulence factors Microbiology QR1-502
spellingShingle	Staphylococcus aureus gene regulation proteases transcriptional regulation virulence factors Microbiology QR1-502 Brittney D. Gimza Maria I. Larias Bridget G. Budny Lindsey N. Shaw Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
description	ABSTRACT A primary function of the extracellular proteases of Staphylococcus aureus is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity to influence the accumulation, or lack thereof, of individual virulence factors. Herein, we comprehensively map this system, exploring the regulation of the four protease loci by known and novel factors. In so doing, we determined that seven major elements (SarS, SarR, Rot, MgrA, CodY, SaeR, and SarA) form the primary network of control, with the latter three being the most powerful. We note that expression of aureolysin is largely repressed by these factors, while the spl operon is subject to the strongest upregulation of any protease loci, particularly by SarR and SaeR. Furthermore, when exploring scpA expression, we find it to be profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). We also present the screening of >100 regulator mutants of S. aureus, identifying 7 additional factors (ArgR2, AtlR, MntR, Rex, XdrA, Rbf, and SarU) that form a secondary circuit of protease control. Primarily, these elements serve as activators, although we reveal XdrA as a new repressor of protease expression. With the exception or ArgR2, each of the new effectors appears to work through the primary network of regulation to influence protease production. Collectively, we present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation and suggest that its existence speaks to the importance of these enzymes to S. aureus physiology and pathogenic potential. IMPORTANCE The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in Staphylococcus aureus.
format	article
author	Brittney D. Gimza Maria I. Larias Bridget G. Budny Lindsey N. Shaw
author_facet	Brittney D. Gimza Maria I. Larias Bridget G. Budny Lindsey N. Shaw
author_sort	Brittney D. Gimza
title	Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_short	Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full	Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_fullStr	Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full_unstemmed	Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_sort	mapping the global network of extracellular protease regulation in <named-content content-type="genus-species">staphylococcus aureus</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/e61be0592ddc48dc8fd0ba1827a35c1e
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Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

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