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1.C.131.  The VasX Toxin (VasX) Family 

VasX, a unique toxin, requires a functional T6SS for secretion. Deletion of vasX does not affect export or enzymatic function of the structural T6SS proteins Hcp and VgrG-1, showing that VasX is dispensable for the assembly and is not a component of the physical translocon complex. VasX localizes to the bacterial membrane, interacts with membrane lipids, and is a virulence factor, as a V. cholerae mutant lacking vasX exhibits a phenotype of attenuated virulence toward Dictyostelium discoideum.(Miyata et al. 2011).

Miyata et al. 2013 described a dual expression profile of the T6SS immunity protein-encoding genes tsiV1, tsiV2, and tsiV3 that provide pandemic V. cholerae strains with T6SS immunity and allows T6SS-silent strains to maintain immunity against attacks by T6SS-active bacterial neighbors. The dual expression profile allows transcription of the three genes encoding immunity proteins independently of other T6SS proteins encoded within the same operon. One of these immunity proteins, TsiV2, protects against the T6SS effector VasX which is encoded immediately upstream of tsiV2. VasX is a secreted, lipid-binding protein. The presence of an internal promoter in the open reading frame of vasX drives expression of the downstream gene tsiV2. Furthermore, VasX acts in conjunction with VasW, an accessory protein to VasX, to compromise the inner membrane of prokaryotic target cells. The dual regulatory profile of the T6SS immunity protein-encoding genes tsiV1, tsiV2, and tsiV3 permits V. cholerae to tightly control T6SS gene expression while maintaining immunity to T6SS activity (Miyata et al. 2013).

By systemically mutating the active sites of 3 Vibrio cholerae effectors, TseL, VasX, and VgrG3, Liang et al. 2019 showed that their physical presence but not their activities is crucial for T6SS assembly. Catalytic mutants of TseL and VgrG3 and truncated VasX mutations abolished the killing of the effector-cognate immunity mutants. The VasX-mediated antimicrobial activity is solely dependent on the C-terminal colicin domain. Removal of the colicin domain abolished VasX secretion and reduced T6SS assembly, while deletion of the colicin internal loop abolished its toxicity but had little effect on secretion and assembly (Liang et al. 2019).

References associated with 1.C.131 family:

Liang, X., F. Kamal, T.T. Pei, P. Xu, J.J. Mekalanos, and T.G. Dong. (2019). An onboard checking mechanism ensures effector delivery of the type VI secretion system in. Proc. Natl. Acad. Sci. USA 116: 23292-23298. 31659021
Miyata, S.T., D. Unterweger, S.P. Rudko, and S. Pukatzki. (2013). Dual expression profile of type VI secretion system immunity genes protects pandemic Vibrio cholerae. PLoS Pathog 9: e1003752. 24348240
Miyata, S.T., M. Kitaoka, T.M. Brooks, S.B. McAuley, and S. Pukatzki. (2011). Vibrio cholerae requires the type VI secretion system virulence factor VasX to kill Dictyostelium discoideum. Infect. Immun. 79: 2941-2949. 21555399