Listeria monocytogenes TcyKLMN Cystine/Cysteine Transporter Facilitates Glutathione Synthesis and Virulence Gene Expression

Moran Brenner, Sivan Friedman, Adi Haber, Nurit Livnat-Levanon, Ilya Borovok, Nadejda Sigal, Oded Lewinson, Anat A. Herskovits

Research output: Contribution to journalArticlepeer-review

Abstract

Listeria monocytogenes is a saprophyte and a human intracellular pathogen. Upon invasion into mammalian cells, it senses multiple metabolic and environmental signals that collectively trigger its transition to the pathogenic state. One of these signals is the tripeptide glutathione, which acts as an allosteric activator of L. monocytogenes’s master virulence regulator, PrfA. While glutathione synthesis by L. monocytogenes was shown to be critical for PrfA activation and virulence gene expression, it remains unclear how this tripeptide is synthesized in changing environments, especially in light of the observation that L. monocytogenes is auxotrophic to one of its precursors, cysteine. Here, we show that the ABC transporter TcyKLMN is a cystine/cysteine importer that supplies cysteine for glutathione synthesis, hence mediating the induction of the virulence genes. Further, we demonstrate that this transporter is negatively regulated by three metabolic regulators, CodY, CymR, and CysK, which sense and respond to changing concentrations of branched-chain amino acids (BCAA) and cysteine. The data indicate that under low concentrations of BCAA, TcyKLMN is upregulated, driving the production of glutathione by supplying cysteine, thereby facilitating PrfA activation. These findings provide molecular insight into the coupling of L. monocytogenes metabolism and virulence, connecting BCAA sensing to cysteine uptake and glutathione biosynthesis as a mechanism that controls virulence gene expression. This study exemplifies how bacterial pathogens sense their intracellular environment and exploit essential metabolites as effectors of virulence.

Original languageEnglish
Pages (from-to)e0044822
JournalmBio
Volume13
Issue number3
DOIs
StatePublished - Jun 2022

Keywords

  • Amino Acids, Branched-Chain/metabolism
  • Animals
  • BCAA
  • Bacterial Proteins/genetics
  • Cysteine/metabolism
  • Cystine/genetics
  • GSH
  • Gene Expression
  • Gene Expression Regulation, Bacterial
  • Glutathione/metabolism
  • Humans
  • KEYWORDS Listeria monocytogenes
  • Listeria monocytogenes
  • Mammals/genetics
  • Membrane Transport Proteins/metabolism
  • Peptide Termination Factors/metabolism
  • Virulence/genetics
  • branched-chain amino acids
  • cysteine importer
  • cystine
  • cystine/cysteine importer
  • glutathione biosynthesis

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Virology

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