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Activity of the Pore-Forming Virulence Factor Listeriolysin O Is Reversibly Inhibited by Naturally Occurring S-Glutathionylation.
Portman, Jonathan L; Huang, Qiongying; Reniere, Michelle L; Iavarone, Anthony T; Portnoy, Daniel A.
Afiliación
  • Portman JL; Graduate Group in Infectious Diseases and Immunity, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
  • Huang Q; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
  • Reniere ML; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
  • Iavarone AT; The California Institute for Quantitative Biosciences and the QB3/Chemistry Mass Spectrometry Facility, University of California, Berkeley, Berkeley, California, USA.
  • Portnoy DA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA portnoy@berkeley.edu.
Infect Immun ; 85(4)2017 04.
Article en En | MEDLINE | ID: mdl-28138025
Cholesterol-dependent cytolysins (CDCs) represent a family of homologous pore-forming proteins secreted by many Gram-positive bacterial pathogens. CDCs mediate membrane binding partly through a conserved C-terminal undecapeptide, which contains a single cysteine residue. While mutational changes to other residues in the undecapeptide typically have severe effects, mutation of the cysteine residue to alanine has minor effects on overall protein function. Thus, the role of this highly conserved reactive cysteine residue remains largely unknown. We report here that the CDC listeriolysin O (LLO), secreted by the facultative intracellular pathogen Listeria monocytogenes, was posttranslationally modified by S-glutathionylation at this conserved cysteine residue and that either endogenously synthesized or exogenously added glutathione was sufficient to form this modification. When recapitulated with purified protein in vitro, this modification completely ablated the activity of LLO, and this inhibitory effect was fully reversible by treatment with reducing agents. A cysteine-to-alanine mutation in LLO rendered the protein completely resistant to inactivation by S-glutathionylation, and a mutant expressing this mutation retained full hemolytic activity. A mutant strain of L. monocytogenes expressing the cysteine-to-alanine variant of LLO was able to infect and replicate within bone marrow-derived macrophages indistinguishably from the wild type in vitro, yet it was attenuated 4- to 6-fold in a competitive murine infection model in vivo This study suggests that S-glutathionylation may represent a mechanism by which CDC-family proteins are posttranslationally modified and regulated and help explain an evolutionary pressure to retain the highly conserved undecapeptide cysteine.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Bacterianas / Factores de Virulencia / Proteínas de Choque Térmico / Proteínas Hemolisinas / Listeria monocytogenes Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Infect Immun Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Bacterianas / Factores de Virulencia / Proteínas de Choque Térmico / Proteínas Hemolisinas / Listeria monocytogenes Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Infect Immun Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos