Structure and regulation of the type VI secretion system

Abstract

The type VI secretion system (T6SS) is a complex and widespread gram-negative bacterial export pathway with the capacity to translocate protein effectors into a diversity of target cell types. Current structural models of the T6SS indicate that the apparatus is composed of at least two complexes, a dynamic bacteriophage-like structure and a cell-envelope-spanning membrane-associated assembly. How these complexes interact to promote effector secretion and cell targeting remains a major question in the field. As a contact-dependent pathway with specific cellular targets, the T6SS is subject to tight regulation. Thus, the identification of regulatory elements that control T6S expression continues to shape our understanding of the environmental circumstances relevant to its function. This review discusses recent progress toward characterizing T6S structure and regulation.

Figure 1

Protein interaction network between type VI secretion subunits. The localization and topologies of the core components of the T6SS are represented. Arrows indicate interactions detected among the subunits by biochemical/structural (blue) or two-hybrid approaches (red). The letter accompanying the arrow denotes the system where the interaction was detected. The membrane-associated subassembly and the bacteriophage-like subassembly are outlined in green and pink, respectively. The question mark represents subunits for which the localization has not been investigated. Relevant studies are discussed in the text. Abbreviations: T6SS, type VI secretion system; A, Agrobacterium tumefaciens; B, Burkholderia cenocepacia; E, Edwardsiella tarda; EA, enteroaggregative Escherichia coli; P, Pseudomonas aeruginosa; S, Salmonella enterica; Sm, Serratia marcescens; V, Vibrio cholerae; Y, Yersinia pseudotuberculosis Please add references (, , , , , , , , , , , , , and 116)

Figure 2

Schematic representation comparing proposed models of bacteriophage T4 and T6S. Homologous and analogous type VI secretion (T6S) and T4 proteins are colored the same as their T4 phage counterparts. (a) The bacteriophage T4 tail tube is surrounded by the tail sheath and terminated by the cell-puncturing device (gp27/gp5). (b) Upon host cell binding, the bacteriophage T4 baseplate undergoes a conformational change that triggers tail sheath contraction and results in puncturing of the outer membrane (OM) and DNA delivery. Models of (c) inactivated and (d) activated states of T6S based on protein localization and interactions between T6S subunits. The three membrane-associated proteins TssL, TssM, and TssJ form a complex bound to the peptidoglycan (PG) layer via TssL. The T6S appendix formed by an Hcp tube and a VgrG trimer is thought to be anchored at the cell envelope by the membrane-associated complex. It has been hypothesized that an assembly baseplate can participate in T6S appendix assembly. (c) TssB and TssC may form a sheath-like structure enclosing the Hcp tube within the periplasmic space. (d) Activation of the T6SS results in effector delivery to a target cell through the Hcp tube. By analogy with bacteriophage T4, the sheath-like structure could propel, through contraction, the Hcp tube toward the cell exterior or directly to the target cell. Abbreviation: IM, inner membrane.

Figure 3

Schematic representation of the diverse regulatory systems that modulate T6S expression and activation in assorted bacteria. Only those regulatory pathways emphasized in this review are depicted. Pathways are labeled A–E corresponding to the order of their presentation in the text. (A) Fur represses T6S transcription in the presence of iron. (B) bEBPs function in conjunction with σ⁵⁴ to activate T6S transcription. (C) The TPP posttranslationally activates T6S in response to surface association. Self- and nonself-derived bacterial signals modulate T6S (D) posttranscriptionally through the Gac/Rsm pathway or (E) transcriptionally via quorum sensing. At right is a target bacterium undergoing intoxication by Tse1–3 effectors (e1–3). Abbreviations: TPP, threonine phosphorylation pathway; bEBP, bacterial enhancer binding protein; T6S, type VI secretion.