Research Article: Francisella tularensis IglG Belongs to a Novel Family of PAAR-Like T6SS Proteins and Harbors a Unique N-terminal Extension Required for Virulence

Date Published: September 7, 2016

Publisher: Public Library of Science

Author(s): Mélanie Rigard, Jeanette E. Bröms, Amandine Mosnier, Maggy Hologne, Amandine Martin, Lena Lindgren, Claire Punginelli, Claire Lays, Olivier Walker, Alain Charbit, Philippe Telouk, Wayne Conlan, Laurent Terradot, Anders Sjöstedt, Thomas Henry, Steven R. Blanke.


The virulence of Francisella tularensis, the etiological agent of tularemia, relies on an atypical type VI secretion system (T6SS) encoded by a genomic island termed the Francisella Pathogenicity Island (FPI). While the importance of the FPI in F. tularensis virulence is clearly established, the precise role of most of the FPI-encoded proteins remains to be deciphered. In this study, using highly virulent F. tularensis strains and the closely related species F. novicida, IglG was characterized as a protein featuring a unique α-helical N-terminal extension and a domain of unknown function (DUF4280), present in more than 250 bacterial species. Three dimensional modeling of IglG and of the DUF4280 consensus protein sequence indicates that these proteins adopt a PAAR-like fold, suggesting they could cap the T6SS in a similar way as the recently described PAAR proteins. The newly identified PAAR-like motif is characterized by four conserved cysteine residues, also present in IglG, which may bind a metal atom. We demonstrate that IglG binds metal ions and that each individual cysteine is required for T6SS-dependent secretion of IglG and of the Hcp homologue, IglC and for the F. novicida intracellular life cycle. In contrast, the Francisella-specific N-terminal α-helical extension is not required for IglG secretion, but is critical for F. novicida virulence and for the interaction of IglG with another FPI-encoded protein, IglF. Altogether, our data suggest that IglG is a PAAR-like protein acting as a bi-modal protein that may connect the tip of the Francisella T6SS with a putative T6SS effector, IglF.

Partial Text

Francisella tularensis is a Gram-negative bacterium that causes tularemia [1]. The severity of tularemia is highly variable depending on the route of inoculation of the bacterium and the infecting strain. F. tularensis subspecies tularensis is the most virulent subspecies with a 50% lethal dose estimated to be at most 10 bacteria by the intranasal route for humans [2]. A Live Vaccine Strain (LVS), derived from a F. tularensis subspecies holarctica strain, is widely used to study the pathogenesis of tularemia. F. novicida is another closely related species, which is avirulent for immunocompetent humans but highly virulent in mice. Due to its ability to reproduce the intracellular life cycle of the more virulent subspecies, F. novicida is widely used as a model system to study tularemia [3].

Despite the well-recognized role of the FPI in Francisella virulence in vitro and in vivo, the function of most of the FPI-encoded proteins is still elusive. The homology between FPI proteins and components of a T6SS [44,45] was described almost 10 years ago [8]. Yet, in spite of tremendous progress in the understanding of T6SS assembly and function in numerous bacterial species [11,14], the translation of this knowledge to the Francisella FPI has been challenging. This difficulty lies in part in the limited similarity of the Francisella FPI with other T6SS [46].




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