Molecular weaponry: diverse effectors delivered by the Type VI secretion system

Abstract

The Type VI secretion system is a widespread bacterial nanomachine, used to deliver toxins directly into eukaryotic or prokaryotic target cells. These secreted toxins, or effectors, act on diverse cellular targets, and their action provides the attacking bacterial cell with a significant fitness advantage, either against rival bacteria or eukaryotic host organisms. In this review, we discuss the delivery of diverse effectors by the Type VI secretion system, the modes of action of the so-called 'anti-bacterial' and 'anti-eukaryotic' effectors, the mechanism of self-resistance against anti-bacterial effectors and the evolutionary implications of horizontal transfer of Type VI secretion system-associated toxins. Whilst it is likely that many more effectors remain to be identified, it is already clear that toxins delivered by this secretion system represent efficient weapons against both bacteria and eukaryotes.

Figure 1

The Type VI secretion system and its action against prokaryotic and eukaryotic target cells. A. Schematic depiction of the T6SS firing into a target cell, with components of the expelled puncturing device highlighted in colour (green, Hcp; red, VgrG; orange, PAAR), and effectors or effector domains shown with stars. Cargo effectors are recruited by interaction with Hcp or VgrG, whereas specialized effectors contain effector domains fused to VgrG or PAAR. B. General representation of an anti‐bacterial T6SS, where multiple toxic effectors attack targets in the periplasm, membrane and/or cytoplasm of a rival bacterial cell, leading to inhibition of growth or lysis. C. Schematic illustrating how the best characterized T6SS‐delivered anti‐eukaryotic effectors interfere with eukaryotic host biological functions. In epithelial cells, P. aeruginosa promotes bacterial internalization by delivering phospholipases PldA and PldB, which induce the activation of the PI3K/Akt pathway, and VgrG2b, which binds to γ‐tubulin ring complex (γTuRC). The Pld proteins bind to Akt and also their enzymatic activity releases phosphatidic acid (PA), which is likely the signal inducing Akt phosphorylation. In phagocytic cells, V. cholerae delivers VgrG‐1 from the phagosome to the cytosol where it inhibits further phagocytosis by cross‐linking actin, whereas Burkholderia utilize another specialized VgrG, VgrG5, to induce host cell membrane fusion, promoting mononuclear giant cell formation and intercellular spread. OM, outer membrane; PG, peptidoglycan; IM, inner membrane.

Figure 2

Anti‐bacterial Type VI secreted effectors: cellular targets and self‐protection mechanism. Schematic depiction of different classes of effector toxins and their sites of action once delivered into a target cell. Because this is a resistant (sibling) cell, specific immunity proteins bind to their cognate effectors in order to neutralize their activity. Dark circles with stars represent effectors, whilst lighter circles represent corresponding immunity proteins. Examples of atomic structures of effector : immunity complexes for four classes of effector are shown in the insets (PDB entries: Tle4^PA/Tli4^PA, 4R1D; VgrG3^VC/TsiV3, 4NOO; Tge1^PA/Tgi1^PA, 4N88 and Tae4.1^SM/Tai4a^SM, 4BI8; Table 1). Black circles represent anti‐bacterial effectors whose function is currently unknown. OM, outer membrane; PG, peptidoglycan cell wall; IM, inner membrane.