Specialized killing across the domains of life by the type VI secretion systems of Pseudomonas aeruginosa

Abstract

Type VI secretion systems (T6SSs) are widespread bacterial protein secretion machines that inject toxic effector proteins into nearby cells, thus facilitating both bacterial competition and virulence. Pseudomonas aeruginosa encodes three evolutionarily distinct T6SSs that each export a unique repertoire of effectors. Owing to its genetic tractability, P. aeruginosa has served as a model organism for molecular studies of the T6SS. However, P. aeruginosa is also an opportunistic pathogen and ubiquitous environmental organism that thrives in a wide range of habitats. Consequently, studies of its T6SSs have provided insight into the role these systems play in the diverse lifestyles of this species. In this review, we discuss recent advances in understanding the regulation and toxin repertoire of each of the three P. aeruginosa T6SSs. We argue that these T6SSs serve distinct physiological functions; whereas one system is a dedicated defensive weapon for interbacterial antagonism, the other two T6SSs appear to function primarily during infection. We find support for this model in examining the signalling pathways that control the expression of each T6SS and co-ordinate the activity of these systems with other P. aeruginosa behaviours. Furthermore, we discuss the effector repertoires of each T6SS and connect the mechanisms by which these effectors kill target cells to the ecological conditions under which their respective systems are activated. Understanding the T6SSs of P. aeruginosa in the context of this organism's diverse lifestyles will provide insight into the physiological roles these secretion systems play in this remarkably adaptable bacterium.

Keywords: Bacterial toxins; Pseudomonas aeruginosa; Type VI secretion systems.

Figure 1. The structure of the T6SS.

(A) Schematic representation of the general T6SS membrane complex and tail tube complex. The baseplate complex that connects these two sub-assemblies has been omitted for clarity. (B) Schematic representation of characterized mechanisms of effector recruitment to the spike complex. While some effectors exist as C-terminal domains (CTD) of proline-alanine-alanine-arginine (PAAR) or valine glycine repeat protein G (VgrG) proteins, others are recruited to the complex by direct interaction or via interactions with an adaptor protein. (C) Cross-sectional representation of the haemolysin co-regulated protein (Hcp) tube containing Hcp-associated effectors.

Figure 2. Regulatory inputs that control T6SS activity under different environmental conditions.

(A) In conditions where P. aeruginosa is not a dominant member of the microbial community, the H1-T6SS serves as a weapon of defensce against incoming threats. The absence of quorum signals induces transcription of H1-T6SS genes, whereas the relative abundance of iron inhibits transcription of the H2- and H3-T6SS loci. Signalling through the Gac/Rsm pathway induces the expression of rsmY and rsmZ, which sequester the RNA-binding protein RsmA and enable the translation of T6SS proteins. Finally, signalling through the threonine phosphorylation pathway co-ordinates H1-T6SS firing with incoming membrane injuries, thus enabling P. aeruginosa to engage in tit-for-tat T6SS behaviour. (B) Under conditions where P. aeruginosa dominates the microbial community, the H2- and H3-T6SSs serve as weapons of co-ordinated attack against non-kin cells or an animal host. Extracellular signals of high P. aeruginosa density and the host environment, such as iron starvation, quorum signals, and extracellular calcium, induce transcription and translation of H2- and H3-T6SS genes via the Gac/Rsm and Fur pathways.