The two-component system WalKR provides an essential link between cell wall homeostasis and DNA replication in Staphylococcus aureus

Liam K.R. Sharkey, Romain Guerillot, Calum J. Walsh, Adrianna M. Turner, Jean Y.H. Lee, Stephanie L. Neville, Stephan Klatt, Sarah L. Baines, Sacha J. Pidot, Fernando J. Rossello, Torsten Seemann, Hamish E.G. McWilliam, Ellie Cho, Glen P. Carter, Benjamin P. Howden, Christopher A. McDevitt, Abderrahman Hachani, Timothy P. Stinear, Ian R. Monk

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7 Citations (Scopus)

Abstract

Among the 16 two-component -y-tem- in the opportuni-tic human pathogen Staphylococcus aureus, only WalKR i- e-ential. Like the orthologou- -y-tem- in other Bacillota, S. aureus WalKR control- autoly-in- involved in peptidoglycan remodeling and i- therefore intimately involved in cell divi-ion. However, de-pite the importance of WalKR in S. aureus, the ba-i- for it- e-entiality i- not under-tood and the regulon i-poorly defined. Here, we defined a con-en-u- WalR DNA-binding motif and the direct WalKR regulon by u-ing functional genomic-, including chromatin immunoprecipitation -equencing, with a panel of i-ogenic walKR mutant- that had a -pectrum of altered activitie-. Con-i-tent with prior finding-, the direct regulon include- multiple autoly-in gene-. However, thi- work al-o revealed that WalR directly regulate- at lea-t five e-ential gene- involved in lipoteichoic acid -ynthe-i- (ltaS): tran-lation (rplK), DNA compaction (hup), initiation of DNA replication (dnaA, hup) and purine nucleotide metaboli-m (prs). Thu-, WalKR in S. aureus -erve- a- a polyfunctional regulator that contribute-to fundamental control over critical cell proce-e- by coordinately linking cell wall homeo-ta-i- with purine bio-ynthe-i-, protein bio-ynthe-i-, and DNA replication. Our finding- further addre- the e-entiality of thi- locu- and highlight the importance of WalKR a- a bona fide target for novel anti-taphylococcal therapeutic-.

Original languageEnglish
Number of pages28
JournalmBio
Volume14
Issue number6
DOIs
Publication statusPublished - Dec 2023

Keywords

  • -plit lucifera-e
  • ChIP-eq
  • CRISPRi
  • DNA compaction
  • DNA replication
  • e-ential gene-
  • regulation of gene expre-ion
  • RNA-eq
  • Staphylococcus aureus
  • two-component regulatory -y-tem-
  • WalKR
  • WalR

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