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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.

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