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Abstract
Bacteria have evolved toxins to outcompete other bacteria or to hijack host cell pathways. One broad family of bacterial polymorphic toxins gathers multidomain proteins with a modular organization, comprising a C-terminal toxin domain fused to a N-terminal domain that adapts to the delivery apparatus. Polymorphic toxins include bacteriocins, contact-dependent growth inhibition systems, and specialized Hcp, VgrG, PAAR or Rhs Type VI secretion (T6SS) components. We recently described and characterized Tre23, a toxin domain fused to a T6SS-associated Rhs protein in Photorhabdus laumondii, Rhs1. Here, we show that Rhs1 forms a complex with the T6SS spike protein VgrG and the EagR chaperone. Using truncation derivatives and cross-linking mass spectrometry, we demonstrate that VgrG-EagR-Rhs1 complex formation requires the VgrG C-terminal β-helix and the Rhs1 N-terminal region. We then report the cryo-electron-microscopy structure of the Rhs1-EagR complex, demonstrating that the Rhs1 central region forms a β-barrel cage-like structure that encapsulates the C-terminal toxin domain, and provide evidence for processing of the Rhs1 protein through aspartyl autoproteolysis. We propose a model for Rhs1 loading on the T6SS, transport and delivery into the target cell.
Highlights
Bacteria have evolved toxins to outcompete other bacteria or to hijack host cell pathways
Repeat proteins are the insecticidal TcB/TcC complex found in entomopathogenic strains such as Photorhabdus, Yersinia, and Serratia that associate with a third subunit, TcA, to assemble a tripartite Tc-toxin complex targeting insect cells[27,28], the antibacterial WapA tRNases encoded on the genomes of Grampositive bacteria, such as Bacillus and Listeria species[15], Ss-Rearrangement hot spots (Rhs)[1] that is essential for the virulence of the fungus Sclerotinia sclerotiorum toward host plants[29], or the teneurins found in higher metazoans and involved in the establishment of neuronal cell connections during embryogenesis[30–33]
We recently showed that the P. laumondii Plu0353 Rhs[1] protein, encoded within a Type VI secretion system (T6SS) gene cluster (Fig. 1a), is delivered by the T6SS and participates in antibacterial competition by inhibiting protein synthesis[51]
Summary
Bacteria have evolved toxins to outcompete other bacteria or to hijack host cell pathways. Polymorphic toxins comprise diverse families including bacteriocins, contactdependent growth inhibition (CDI) CdiA, Multiple adhesin family (Maf), Rearrangement hot spots (Rhs), and specialized type VI secretion system (T6SS) Hcp, VgrG, and PAAR proteins[1–9]. Repeat proteins are the insecticidal TcB/TcC complex found in entomopathogenic strains such as Photorhabdus, Yersinia, and Serratia that associate with a third subunit, TcA, to assemble a tripartite Tc-toxin complex targeting insect cells[27,28], the antibacterial WapA tRNases encoded on the genomes of Grampositive bacteria, such as Bacillus and Listeria species[15], Ss-Rhs[1] that is essential for the virulence of the fungus Sclerotinia sclerotiorum toward host plants[29], or the teneurins found in higher metazoans and involved in the establishment of neuronal cell connections during embryogenesis[30–33].
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