Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase

ABSTRACT Type II toxin-antitoxin (TA) modules encode a stable toxin that inhibits cell growth and an unstable protein antitoxin that neutralizes the toxin by direct protein-protein contact. hipBA of Escherichia coli strain K-12 codes for HipA, a serine-threonine kinase that phosphorylates and inhibi...

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Autores principales:	Stine Vang Nielsen, Kathryn Jane Turnbull, Mohammad Roghanian, Rene Bærentsen, Maja Semanjski, Ditlev E. Brodersen, Boris Macek, Kenn Gerdes
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	persistence ppGpp toxin/antitoxin systems translation tRNA synthetase Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7a936f4f05fe4d779f30afaf9f227b84
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spelling	oai:doaj.org-article:7a936f4f05fe4d779f30afaf9f227b842021-11-15T15:55:25ZSerine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase10.1128/mBio.01138-192150-7511https://doaj.org/article/7a936f4f05fe4d779f30afaf9f227b842019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01138-19https://doaj.org/toc/2150-7511ABSTRACT Type II toxin-antitoxin (TA) modules encode a stable toxin that inhibits cell growth and an unstable protein antitoxin that neutralizes the toxin by direct protein-protein contact. hipBA of Escherichia coli strain K-12 codes for HipA, a serine-threonine kinase that phosphorylates and inhibits glutamyl-tRNA synthetase. Induction of hipA inhibits charging of glutamyl-tRNA that, in turn, inhibits translation and induces RelA-dependent (p)ppGpp synthesis and multidrug tolerance. Here, we describe the discovery of a three-component TA gene family that encodes toxin HipT, which exhibits sequence similarity with the C-terminal part of HipA. A genetic screening revealed that trpS in high copy numbers suppresses HipT-mediated growth inhibition. We show that HipT of E. coli O127 is a kinase that phosphorylates tryptophanyl-tRNA synthetase in vitro at a conserved serine residue. Consistently, induction of hipT inhibits cell growth and stimulates production of (p)ppGpp. The gene immediately upstream from hipT, called hipS, encodes a small protein that exhibits sequence similarity with the N terminus of HipA. HipT kinase was neutralized by cognate HipS in vivo, whereas the third component, HipB, encoded by the first gene of the operon, did not counteract HipT kinase activity. However, HipB augmented the ability of HipS to neutralize HipT. Analysis of two additional hipBST-homologous modules showed that, indeed, HipS functions as an antitoxin in these cases also. Thus, hipBST constitutes a novel family of tricomponent TA modules where hipA has been split into two genes, hipS and hipT, that function as a novel type of TA pair. IMPORTANCE Bacterial toxin-antitoxin (TA) modules confer multidrug tolerance (persistence) that may contribute to the recalcitrance of chronic and recurrent infections. The first high-persister gene identified was hipA of Escherichia coli strain K-12, which encodes a kinase that inhibits glutamyl-tRNA synthetase. The hipA gene encodes the toxin of the hipBA TA module, while hipB encodes an antitoxin that counteracts HipA. Here, we describe a novel, widespread TA gene family, hipBST, that encodes HipT, which exhibits sequence similarity with the C terminus of HipA. HipT is a kinase that phosphorylates tryptophanyl-tRNA synthetase and thereby inhibits translation and induces the stringent response. Thus, this new TA gene family may contribute to the survival and spread of bacterial pathogens.Stine Vang NielsenKathryn Jane TurnbullMohammad RoghanianRene BærentsenMaja SemanjskiDitlev E. BrodersenBoris MacekKenn GerdesAmerican Society for MicrobiologyarticlepersistenceppGpptoxin/antitoxin systemstranslationtRNA synthetaseMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	persistence ppGpp toxin/antitoxin systems translation tRNA synthetase Microbiology QR1-502
spellingShingle	persistence ppGpp toxin/antitoxin systems translation tRNA synthetase Microbiology QR1-502 Stine Vang Nielsen Kathryn Jane Turnbull Mohammad Roghanian Rene Bærentsen Maja Semanjski Ditlev E. Brodersen Boris Macek Kenn Gerdes Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase
description	ABSTRACT Type II toxin-antitoxin (TA) modules encode a stable toxin that inhibits cell growth and an unstable protein antitoxin that neutralizes the toxin by direct protein-protein contact. hipBA of Escherichia coli strain K-12 codes for HipA, a serine-threonine kinase that phosphorylates and inhibits glutamyl-tRNA synthetase. Induction of hipA inhibits charging of glutamyl-tRNA that, in turn, inhibits translation and induces RelA-dependent (p)ppGpp synthesis and multidrug tolerance. Here, we describe the discovery of a three-component TA gene family that encodes toxin HipT, which exhibits sequence similarity with the C-terminal part of HipA. A genetic screening revealed that trpS in high copy numbers suppresses HipT-mediated growth inhibition. We show that HipT of E. coli O127 is a kinase that phosphorylates tryptophanyl-tRNA synthetase in vitro at a conserved serine residue. Consistently, induction of hipT inhibits cell growth and stimulates production of (p)ppGpp. The gene immediately upstream from hipT, called hipS, encodes a small protein that exhibits sequence similarity with the N terminus of HipA. HipT kinase was neutralized by cognate HipS in vivo, whereas the third component, HipB, encoded by the first gene of the operon, did not counteract HipT kinase activity. However, HipB augmented the ability of HipS to neutralize HipT. Analysis of two additional hipBST-homologous modules showed that, indeed, HipS functions as an antitoxin in these cases also. Thus, hipBST constitutes a novel family of tricomponent TA modules where hipA has been split into two genes, hipS and hipT, that function as a novel type of TA pair. IMPORTANCE Bacterial toxin-antitoxin (TA) modules confer multidrug tolerance (persistence) that may contribute to the recalcitrance of chronic and recurrent infections. The first high-persister gene identified was hipA of Escherichia coli strain K-12, which encodes a kinase that inhibits glutamyl-tRNA synthetase. The hipA gene encodes the toxin of the hipBA TA module, while hipB encodes an antitoxin that counteracts HipA. Here, we describe a novel, widespread TA gene family, hipBST, that encodes HipT, which exhibits sequence similarity with the C terminus of HipA. HipT is a kinase that phosphorylates tryptophanyl-tRNA synthetase and thereby inhibits translation and induces the stringent response. Thus, this new TA gene family may contribute to the survival and spread of bacterial pathogens.
format	article
author	Stine Vang Nielsen Kathryn Jane Turnbull Mohammad Roghanian Rene Bærentsen Maja Semanjski Ditlev E. Brodersen Boris Macek Kenn Gerdes
author_facet	Stine Vang Nielsen Kathryn Jane Turnbull Mohammad Roghanian Rene Bærentsen Maja Semanjski Ditlev E. Brodersen Boris Macek Kenn Gerdes
author_sort	Stine Vang Nielsen
title	Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase
title_short	Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase
title_full	Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase
title_fullStr	Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase
title_full_unstemmed	Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase
title_sort	serine-threonine kinases encoded by split <italic toggle="yes">hipa</italic> homologs inhibit tryptophanyl-trna synthetase
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/7a936f4f05fe4d779f30afaf9f227b84
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Serine-Threonine Kinases Encoded by Split <italic toggle="yes">hipA</italic> Homologs Inhibit Tryptophanyl-tRNA Synthetase

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