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Serine-Threonine Kinases Encoded by Split hipA Homologs Inhibit Tryptophanyl-tRNA Synthetase
Centre for Bacterial Stress Response and Persistence, Section for Functional Genomics, Department of Biology, University of Copenhagen, Copenhagen, Denmark.ORCID iD: 0000-0002-0899-974X
Centre for Bacterial Stress Response and Persistence, Section for Functional Genomics, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
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2019 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, no 3, article id e01138-19Article in journal (Refereed) Published
Abstract [en]

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 serinethreonine 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 hipBSThomologous 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.

Place, publisher, year, edition, pages
American Society for Microbiology , 2019. Vol. 10, no 3, article id e01138-19
Keywords [en]
persistence, ppGpp, toxin/antitoxin systems, translation, tRNA synthetase
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-167019DOI: 10.1128/mBio.01138-19ISI: 000473596500101PubMedID: 31213559OAI: oai:DiVA.org:umu-167019DiVA, id: diva2:1383604
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Novo NordiskAvailable from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-08Bibliographically approved

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Turnbull, Kathryn JaneRoghanian, MohammadBrodersen, Ditlev E.Gerdes, Kenn
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