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A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow

c-di-GMP primarily controls motile to sessile transitions in bacteria. Diguanylate cyclases (DGCs) catalyze the synthesis of c-di-GMP from two GTP molecules. Typically, bacteria encode multiple DGCs that are activated by specific environmental signals. Their catalytic activity is modulated by c-di-G...

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Detalles Bibliográficos
Autores principales: Hwang, YuneSahng, Harshey, Rasika M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127611/
https://www.ncbi.nlm.nih.gov/pubmed/37036337
http://dx.doi.org/10.1128/mbio.00619-23
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author Hwang, YuneSahng
Harshey, Rasika M.
author_facet Hwang, YuneSahng
Harshey, Rasika M.
author_sort Hwang, YuneSahng
collection PubMed
description c-di-GMP primarily controls motile to sessile transitions in bacteria. Diguanylate cyclases (DGCs) catalyze the synthesis of c-di-GMP from two GTP molecules. Typically, bacteria encode multiple DGCs that are activated by specific environmental signals. Their catalytic activity is modulated by c-di-GMP binding to autoinhibitory sites (I-sites). YfiN is a conserved inner membrane DGC that lacks these sites. Instead, YfiN activity is directly repressed by periplasmic YfiR, which is inactivated by redox stress. In Escherichia coli, an additional envelope stress causes YfiN to relocate to the mid-cell to inhibit cell division by interacting with the division machinery. Here, we report a third activity for YfiN in E. coli, where cell growth is inhibited without YfiN relocating to the division site. This action of YfiN is only observed when the bacteria are cultured on gluconeogenic carbon sources, and is dependent on absence of the autoinhibitory sites. Restoration of I-site function relieves the growth-arrest phenotype, and disabling this function in a heterologous DGC causes acquisition of this phenotype. Arrested cells are tolerant to a wide range of antibiotics. We show that the likely cause of growth arrest is depletion of cellular GTP from run-away synthesis of c-di-GMP, explaining the dependence of growth arrest on gluconeogenic carbon sources that exhaust more GTP during production of glucose. This is the first report of c-di-GMP-mediated growth arrest by altering metabolic flow.
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spelling pubmed-101276112023-04-26 A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow Hwang, YuneSahng Harshey, Rasika M. mBio Research Article c-di-GMP primarily controls motile to sessile transitions in bacteria. Diguanylate cyclases (DGCs) catalyze the synthesis of c-di-GMP from two GTP molecules. Typically, bacteria encode multiple DGCs that are activated by specific environmental signals. Their catalytic activity is modulated by c-di-GMP binding to autoinhibitory sites (I-sites). YfiN is a conserved inner membrane DGC that lacks these sites. Instead, YfiN activity is directly repressed by periplasmic YfiR, which is inactivated by redox stress. In Escherichia coli, an additional envelope stress causes YfiN to relocate to the mid-cell to inhibit cell division by interacting with the division machinery. Here, we report a third activity for YfiN in E. coli, where cell growth is inhibited without YfiN relocating to the division site. This action of YfiN is only observed when the bacteria are cultured on gluconeogenic carbon sources, and is dependent on absence of the autoinhibitory sites. Restoration of I-site function relieves the growth-arrest phenotype, and disabling this function in a heterologous DGC causes acquisition of this phenotype. Arrested cells are tolerant to a wide range of antibiotics. We show that the likely cause of growth arrest is depletion of cellular GTP from run-away synthesis of c-di-GMP, explaining the dependence of growth arrest on gluconeogenic carbon sources that exhaust more GTP during production of glucose. This is the first report of c-di-GMP-mediated growth arrest by altering metabolic flow. American Society for Microbiology 2023-04-10 /pmc/articles/PMC10127611/ /pubmed/37036337 http://dx.doi.org/10.1128/mbio.00619-23 Text en Copyright © 2023 Hwang and Harshey. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Hwang, YuneSahng
Harshey, Rasika M.
A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow
title A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow
title_full A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow
title_fullStr A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow
title_full_unstemmed A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow
title_short A Second Role for the Second Messenger Cyclic-di-GMP in E. coli: Arresting Cell Growth by Altering Metabolic Flow
title_sort second role for the second messenger cyclic-di-gmp in e. coli: arresting cell growth by altering metabolic flow
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127611/
https://www.ncbi.nlm.nih.gov/pubmed/37036337
http://dx.doi.org/10.1128/mbio.00619-23
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