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Title: Glutathionylation of Yersinia pestis LcrV and Its Effects on Plague Pathogenesis

Journal Article · · mBio (Online)
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  1. Argonne National Lab. (ANL), Argonne, IL (United States). Howard T. Ricketts Laboratory; Univ. of Chicago, IL (United States). Dept. of Microbiology
  2. Univ. of California, Los Angeles, CA (United States). Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, Semel Institute of Neuroscience and Human Behavior, David Geffen School of Medicine
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Glutathionylation, the formation of reversible mixed disulfides between glutathione and protein cysteine residues, is a posttranslational modification previously observed for intracellular proteins of bacteria. Here we show thatYersinia pestisLcrV, a secreted protein capping the type III secretion machine, is glutathionylated at Cys273and that this modification promotes association with host ribosomal protein S3 (RPS3), moderatesY. pestistype III effector transport and killing of macrophages, and enhances bubonic plague pathogenesis in mice and rats. Secreted LcrV was purified and analyzed by mass spectrometry to reveal glutathionylation, a modification that is abolished by the codon substitution Cys273Ala inlcrV. Moreover, thelcrVC273Amutation enhanced the survival of animals in models of bubonic plague. Investigating the molecular mechanism responsible for these virulence attributes, we identified macrophage RPS3 as a ligand of LcrV, an association that is perturbed by the Cys273Ala substitution. Furthermore, macrophages infected by thelcrVC273Avariant displayed accelerated apoptotic death and diminished proinflammatory cytokine release. Deletion ofgshB, which encodes glutathione synthetase ofY. pestis, resulted in undetectable levels of intracellular glutathione, and we used aY. pestisΔgshBmutant to characterize the biochemical pathway of LcrV glutathionylation, establishing that LcrV is modified after its transport to the type III needle via disulfide bond formation with extracellular oxidized glutathione. IMPORTANCEYersinia pestis, the causative agent of plague, has killed large segments of the human population; however, the molecular bases for the extraordinary virulence attributes of this pathogen are not well understood. We show here that LcrV, the cap protein of bacterial type III secretion needles, is modified by host glutathione and that this modification contributes to the high virulence ofY. pestisin mouse and rat models for bubonic plague. These data suggest thatY. pestisexploits glutathione in host tissues to activate a virulence strategy, thereby accelerating plague pathogenesis.

Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1626116
Journal Information:
mBio (Online), Vol. 8, Issue 3; ISSN 2150-7511
Publisher:
American Society for MicrobiologyCopyright Statement
Country of Publication:
United States
Language:
English

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