Abstract
Host-targeting type IV secretion systems (T4SS) evolved from conjugative T4SS machineries that mediate interbacterial plasmid transfer. However, the origins of effectors secreted by these virulence devices have remained largely elusive. Previous work showed that some effectors exhibit homology to toxins of bacterial toxin-antitoxin modules, but the evolutionary trajectories underlying these ties had not been resolved. We previously reported that FicT toxins of FicTA toxin-antitoxin modules disrupt cellular DNA topology via their enzymatic FIC (filamentation induced by cAMP) domain. Intriguingly, the FIC domain of the FicT toxin VbhT of Bartonella schoenbuchensis is fused to a type IV secretion signal–the BID (Bep intracellular delivery) domain—similar to the Bartonella effector proteins (Beps) that are secreted into eukaryotic host cells via the host-targeting VirB T4SS. In this study, we show that the VbhT toxin is an interbacterial effector protein secreted via the conjugative Vbh T4SS that is closely related to the VirB T4SS and encoded by plasmid pVbh of B. schoenbuchensis. We therefore propose that the Vbh T4SS together with its effector VbhT represent an evolutionary missing link on a path that leads from a regular conjugation system and FicTA toxin-antitoxin modules to the VirB T4SS and the Beps. Intriguingly, phylogenetic analyses revealed that the fusion of FIC and BID domains has probably occurred independently in VbhT and the common ancestor of the Beps, suggesting parallel evolutionary paths. Moreover, several other examples of TA module toxins that are bona fide substrates of conjugative T4SS indicate that their recruitment as interbacterial effectors is prevalent and serves yet unknown biological functions in the context of bacterial conjugation. We propose that the adaptation for interbacterial transfer favors the exaptation of FicT and other TA module toxins as inter-kingdom effectors and may thus constitute an important stepping stone in the evolution of host-targeted effector proteins.
Highlights
The virulence of many bacterial pathogens depends on effector proteins that are translocated by dedicated secretion systems into eukaryotic host cells where they manipulate various processes in favor of the bacterium [1]
In this article we studied the evolutionary history of a host-targeting effector secretion system of the mammalian pathogen Bartonella that belongs to a group of machineries descended from secretion systems originally mediating DNA transfer between bacterial cells
We found that such a DNA transfer machinery closely related to the host-targeting secretion system of Bartonella has recruited a bacterial protein involved in modulating DNA topology as an interbacterial effector protein that is translocated together with the DNA into recipient cells
Summary
The virulence of many bacterial pathogens depends on effector proteins that are translocated by dedicated secretion systems into eukaryotic host cells where they manipulate various processes in favor of the bacterium [1]. Host-targeting T4SS machineries have evolved various times independently from bacterial conjugation systems, i.e., from T4SS machineries that mediate the interbacterial transfer of plasmids [2, 13]. The VirB T4SS of Bartonella is the sister group of a putative conjugation system called VirB-homologous (Vbh) T4SS found on plasmids scattered over the genus Bartonella [10, 11, 14, 15]. Apart from the T4SS apparatus, conjugative plasmid transfer depends on a DNA processing and transfer (Dtr) machinery based on a protein called relaxase that is the actual substrate of the conjugative T4SS and gets covalently linked to the plasmid DNA prior to secretion. A type IV secretion coupling protein (T4CP) links Dtr and T4SS functionalities by mediating substrate selection for the T4SS machinery (recently reviewed by reference [13])
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