title: Host Cytosolic Glutathione Sensing by a Membrane Histidine Kinase Activates the Type VI Secretion System in an Intracellular Bacterium.
abstract: Type VI secretion systems (T6SSs) are major virulence mechanisms in many Gram-negative bacteria, but the physiological signals that activate them are not well understood. The T6SS1 of Burkholderia pseudomallei is essential for pathogenesis in mammalian hosts and is only expressed when the bacterium is intracellular. We found that signals for T6SS1 activation reside in the host cytosol. Through site-directed mutagenesis and biochemical studies, we identified low molecular weight thiols, particularly glutathione, as the signal sensed by a periplasmic cysteine residue (C62) on the histidine kinase sensor VirA. Upon glutathione exposure, dimeric VirA is converted to monomers via reduction at C62. When glutathione in the host was depleted, T6SS1 expression was abrogated, and bacteria could no longer induce multinucleate giant cell formation, the hallmark of T6SS1 function. Therefore, intracellular bacteria exploit the abundance of glutathione in host cytosol as a signal for expression of virulence at the appropriate time and place.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore. MD7, 8 Medical Drive, Singapore 117597, Singapore.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Wong
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore. MD7, 8 Medical Drive, Singapore 117597, Singapore.
authors.forename: Yahua
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore. MD7, 8 Medical Drive, Singapore 117597, Singapore. Electronic address: bchganyh@nus.edu.sg.
authors.forename: Yunn-Hwen
authors.initials: YH
authors.lastname: Gan
mesh_terms: D000818:Animals; D016957:Burkholderia pseudomallei / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D003600:Cytosol / Q000737:chemistry*; D005978:Glutathione / Q000378:metabolism*; D000071677:Histidine Kinase; D054884:Host-Pathogen Interactions; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D011494:Protein Kinases / Q000378:metabolism*; D055503:Protein Multimerization; D000069376:Type VI Secretion Systems; D014774:Virulence
chemical_list: D008565:Membrane Proteins; D000069376:Type VI Secretion Systems; D011494:Protein Kinases; D000071677:Histidine Kinase; D005978:Glutathione