Type VI Secretion System: A Modular Toolkit for Bacterial Dominance

Abstract

Bacteria use toxin delivery systems, such as the type VI secretion system (T6SS), to antagonize competitors. The T6SS transports toxins, called effectors, directly into recipient cells. In the absence of cognate immunity proteins that protect against kin-intoxication, these effectors target conserved and essential cell components resulting in growth arrest or cell death. Here, we focus on antibacterial T6SS effectors and explore their different activities, modes of delivery, and the domains and proteins that are associated with them to provide a modular and dynamic toxin arsenal. We conclude that these natural machines present a lucrative pool and platform for future antibacterial treatments.

A Superfamily of T6SS Antibacterial Effectors Displaying L,D-carboxypeptidase Activity Towards Peptidoglycan

“…T6SSs translocate effectors by decorating the Hcp-VgrG-PAAR puncturing device. (Cianfanelli et al, 2016; Jana and Salomon, 2019). Small effector proteins composed of only one toxic domain, such as Tae5 STM , usually interact with Hcp proteins for secretion as their size favors fitting inside the narrow tube formed by Hcp hexamers (Silverman et al, 2013; Jana and Salomon, 2019).…”

“…(Cianfanelli et al, 2016; Jana and Salomon, 2019). Small effector proteins composed of only one toxic domain, such as Tae5 STM , usually interact with Hcp proteins for secretion as their size favors fitting inside the narrow tube formed by Hcp hexamers (Silverman et al, 2013; Jana and Salomon, 2019). Further supporting this notion, our bioinformatic analysis showed members of the three families Tae5, Tae6 and Tae7 associated with orphan Hcp proteins (Figure 4C).…”

“…The spear is composed of Hcp (hemolysin co-regulated protein) hexamers capped with a trimer of VgrG (valine-glycine repeat protein G) proteins and a PAAR (proline-alanine-alanine-arginine) protein tip (Mougous et al, 2006; Renault et al, 2018; Shneider et al, 2013). Cargo effector proteins associate through non-covalent interactions with these structural components, while specialized effectors are presented as additional C-terminal domains fused to Hcp, VgrG, or PAAR protein (Cianfanelli et al, 2016; Jana and Salomon, 2019). Consequently, along with the Hcp-VgrG-PAAR puncturing device, a cocktail of effectors is delivered into the target cell after each contraction event.…”

Attenuation of Vibrio parahaemolyticus Virulence Factors by a Mixture of Natural Antimicrobials

“…The Type VI secretion systems (T6SS) are associated with severe forms of gastrointestinal diseases and have been described mostly in Gram-negative bacteria [9]. Bacteria use these secretion systems to eliminate competing microorganisms by transporting toxins into target bacteria or eukaryotic cells, leading to a reduction in growth and ultimately death [10]. Coincidentally, the T6SS was first discovered in Vibrio cholerae [11] and it was characterised by being responsible for the secretion of haemolysin protein (hcp), an important virulence factor in many bacteria, including Pseudomonas aeruginosa [12].…”

A comparative genomics methodology reveals a widespread family of membrane-disrupting T6SS effectors

“…They may also fail to identify effectors that are expressed and delivered in low amounts under the examined experimental conditions. Computational approaches, including analyses of genes found inside T6SS clusters and auxiliary modules 14,20,[26][27][28][29] , genes encoding proteins with T6SS marker domain (e.g., MIX and FIX) 17,23,26 , or genes that neighbor T6SS adapters (e.g., DUF4123, DUF1795, and DUF2169) 13,15,19,[30][31][32] , have resulted in the discovery of many effector families that have proven useful in preliminary analyses of new bacterial genomes 33 . However, such bioinformatic approaches may fail to identify "orphan effectors" that do not neighbor any known T6SS component on the genome, and that do not contain any known T6SS-associated domain.…”