Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response

ABSTRACT The cell wall is a strong, yet flexible, meshwork of peptidoglycan (PG) that gives a bacterium structural integrity. To accommodate a growing cell, the wall is remodeled by both PG synthesis and degradation. Vibrio cholerae encodes a group of three nearly identical zinc-dependent endopeptid...

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Autores principales:	Shannon G. Murphy, Laura Alvarez, Myfanwy C. Adams, Shuning Liu, Joshua S. Chappie, Felipe Cava, Tobias Dörr
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Gram-negative Vibrio cholerae cell wall hydrolase metalloproteins peptidoglycan Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d54ff4385d3043f3ae4d38d4725f1097
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spelling	oai:doaj.org-article:d54ff4385d3043f3ae4d38d4725f10972021-11-15T15:55:13ZEndopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response10.1128/mBio.02620-182150-7511https://doaj.org/article/d54ff4385d3043f3ae4d38d4725f10972019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02620-18https://doaj.org/toc/2150-7511ABSTRACT The cell wall is a strong, yet flexible, meshwork of peptidoglycan (PG) that gives a bacterium structural integrity. To accommodate a growing cell, the wall is remodeled by both PG synthesis and degradation. Vibrio cholerae encodes a group of three nearly identical zinc-dependent endopeptidases (EPs) that are predicted to hydrolyze PG to facilitate cell growth. Two of these (ShyA and ShyC) are conditionally essential housekeeping EPs, while the third (ShyB) is not expressed under standard laboratory conditions. To investigate the role of ShyB, we conducted a transposon screen to identify mutations that activate shyB transcription. We found that shyB is induced as part of the Zur-mediated zinc starvation response, a mode of regulation not previously reported for cell wall lytic enzymes. In vivo, ShyB alone was sufficient to sustain cell growth in low-zinc environments. In vitro, ShyB retained its d,d-endopeptidase activity against purified sacculi in the presence of the metal chelator EDTA at concentrations that inhibit ShyA and ShyC. This insensitivity to metal chelation is likely what enables ShyB to substitute for other EPs during zinc starvation. Our survey of transcriptomic data from diverse bacteria identified other candidate Zur-regulated EPs, suggesting that this adaptation to zinc starvation is employed by other Gram-negative bacteria. IMPORTANCE Bacteria encode a variety of adaptations that enable them to survive during zinc starvation, a condition which is encountered both in natural environments and inside the human host. In Vibrio cholerae, the causative agent of the diarrheal disease cholera, we have identified a novel member of this zinc starvation response, a cell wall hydrolase that retains function and is conditionally essential for cell growth in low-zinc environments. Other Gram-negative bacteria contain homologs that appear to be under similar regulatory control. These findings are significant because they represent, to our knowledge, the first evidence that zinc homeostasis influences cell wall turnover. Anti-infective therapies commonly target the bacterial cell wall; therefore, an improved understanding of how the cell wall adapts to host-induced zinc starvation could lead to new antibiotic development. Such therapeutic interventions are required to combat the rising threat of drug-resistant infections.Shannon G. MurphyLaura AlvarezMyfanwy C. AdamsShuning LiuJoshua S. ChappieFelipe CavaTobias DörrAmerican Society for MicrobiologyarticleGram-negativeVibrio choleraecell wallhydrolasemetalloproteinspeptidoglycanMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Gram-negative Vibrio cholerae cell wall hydrolase metalloproteins peptidoglycan Microbiology QR1-502
spellingShingle	Gram-negative Vibrio cholerae cell wall hydrolase metalloproteins peptidoglycan Microbiology QR1-502 Shannon G. Murphy Laura Alvarez Myfanwy C. Adams Shuning Liu Joshua S. Chappie Felipe Cava Tobias Dörr Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response
description	ABSTRACT The cell wall is a strong, yet flexible, meshwork of peptidoglycan (PG) that gives a bacterium structural integrity. To accommodate a growing cell, the wall is remodeled by both PG synthesis and degradation. Vibrio cholerae encodes a group of three nearly identical zinc-dependent endopeptidases (EPs) that are predicted to hydrolyze PG to facilitate cell growth. Two of these (ShyA and ShyC) are conditionally essential housekeeping EPs, while the third (ShyB) is not expressed under standard laboratory conditions. To investigate the role of ShyB, we conducted a transposon screen to identify mutations that activate shyB transcription. We found that shyB is induced as part of the Zur-mediated zinc starvation response, a mode of regulation not previously reported for cell wall lytic enzymes. In vivo, ShyB alone was sufficient to sustain cell growth in low-zinc environments. In vitro, ShyB retained its d,d-endopeptidase activity against purified sacculi in the presence of the metal chelator EDTA at concentrations that inhibit ShyA and ShyC. This insensitivity to metal chelation is likely what enables ShyB to substitute for other EPs during zinc starvation. Our survey of transcriptomic data from diverse bacteria identified other candidate Zur-regulated EPs, suggesting that this adaptation to zinc starvation is employed by other Gram-negative bacteria. IMPORTANCE Bacteria encode a variety of adaptations that enable them to survive during zinc starvation, a condition which is encountered both in natural environments and inside the human host. In Vibrio cholerae, the causative agent of the diarrheal disease cholera, we have identified a novel member of this zinc starvation response, a cell wall hydrolase that retains function and is conditionally essential for cell growth in low-zinc environments. Other Gram-negative bacteria contain homologs that appear to be under similar regulatory control. These findings are significant because they represent, to our knowledge, the first evidence that zinc homeostasis influences cell wall turnover. Anti-infective therapies commonly target the bacterial cell wall; therefore, an improved understanding of how the cell wall adapts to host-induced zinc starvation could lead to new antibiotic development. Such therapeutic interventions are required to combat the rising threat of drug-resistant infections.
format	article
author	Shannon G. Murphy Laura Alvarez Myfanwy C. Adams Shuning Liu Joshua S. Chappie Felipe Cava Tobias Dörr
author_facet	Shannon G. Murphy Laura Alvarez Myfanwy C. Adams Shuning Liu Joshua S. Chappie Felipe Cava Tobias Dörr
author_sort	Shannon G. Murphy
title	Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response
title_short	Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response
title_full	Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response
title_fullStr	Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response
title_full_unstemmed	Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response
title_sort	endopeptidase regulation as a novel function of the zur-dependent zinc starvation response
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d54ff4385d3043f3ae4d38d4725f1097
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Endopeptidase Regulation as a Novel Function of the Zur-Dependent Zinc Starvation Response

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