Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance

Abstract Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jan Felix, Claire Siebert, Julia Novion Ducassou, Jérôme Nigou, Pierre Simon Garcia, Angélique Fraudeau, Karine Huard, Caroline Mas, Céline Brochier-Armanet, Yohann Couté, Irina Gutsche, Patricia Renesto
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bf9733d66c7542f68a83f9b9f0353881
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:bf9733d66c7542f68a83f9b9f0353881
record_format	dspace
spelling	oai:doaj.org-article:bf9733d66c7542f68a83f9b9f03538812021-12-02T15:23:05ZStructural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance10.1038/s41598-020-79611-52045-2322https://doaj.org/article/bf9733d66c7542f68a83f9b9f03538812021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79611-5https://doaj.org/toc/2045-2322Abstract Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.Jan FelixClaire SiebertJulia Novion DucassouJérôme NigouPierre Simon GarciaAngélique FraudeauKarine HuardCaroline MasCéline Brochier-ArmanetYohann CoutéIrina GutschePatricia RenestoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jan Felix Claire Siebert Julia Novion Ducassou Jérôme Nigou Pierre Simon Garcia Angélique Fraudeau Karine Huard Caroline Mas Céline Brochier-Armanet Yohann Couté Irina Gutsche Patricia Renesto Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance
description	Abstract Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.
format	article
author	Jan Felix Claire Siebert Julia Novion Ducassou Jérôme Nigou Pierre Simon Garcia Angélique Fraudeau Karine Huard Caroline Mas Céline Brochier-Armanet Yohann Couté Irina Gutsche Patricia Renesto
author_facet	Jan Felix Claire Siebert Julia Novion Ducassou Jérôme Nigou Pierre Simon Garcia Angélique Fraudeau Karine Huard Caroline Mas Céline Brochier-Armanet Yohann Couté Irina Gutsche Patricia Renesto
author_sort	Jan Felix
title	Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance
title_short	Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance
title_full	Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance
title_fullStr	Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance
title_full_unstemmed	Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance
title_sort	structural and functional analysis of the francisella lysine decarboxylase as a key actor in oxidative stress resistance
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/bf9733d66c7542f68a83f9b9f0353881
work_keys_str_mv	AT janfelix structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT clairesiebert structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT julianovionducassou structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT jeromenigou structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT pierresimongarcia structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT angeliquefraudeau structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT karinehuard structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT carolinemas structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT celinebrochierarmanet structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT yohanncoute structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT irinagutsche structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance AT patriciarenesto structuralandfunctionalanalysisofthefrancisellalysinedecarboxylaseasakeyactorinoxidativestressresistance
_version_	1718387351007264768

Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance

Ejemplares similares