Coordinated delivery and function of bacterial MARTX toxin effectors

Abstract

Bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include toxins counteracting or amplifying effects of another toxin or though regulating the stability of virulence factors to remove their function once it is no longer needed. Multifunctional autoprocessing repeats-in toxin (MARTX) toxins are effector delivery toxins that form a pore into the plasma membrane of a eukaryotic cell to deliver multiple effector proteins into the cytosol of the target cell. The function of these proteins includes manipulating actin cytoskeletal dynamics, regulating signal transduction pathways and inhibiting host secretory pathways. Investigations into the molecular mechanisms of these effector domains are providing insight into how the function of some effectors overlap and regulate one another during infection. Coordinated crosstalk of effector function suggests that MARTX toxins are not simply a sum of all their parts. Instead, modulation of cell function by effector domains may depend on which other effector domain are co-delivered. Future studies will elucidate how these effectors interact with each other to modulate the bacterial host interaction.

The Vibrio cholerae MARTX toxin simultaneously induces actin collapse while silencing the inflammatory response to cytoskeletal damage

“…The MARTXVc toxin has four putative cytotoxic functions: the formation of a pore and the biochemical activities of its three effector domains (9). In previous studies (2), a derivative of KFV119 was generated in which the rtxA gene was modified to replace the sequences that encode the effector domains with an inframe sequence for b-lactamase (Bla).…”

“…Due to this enzymatic multifunctionality, MARTX toxins have been described as bacterial "cluster bombs" that release multiple cytotoxic bomblets into host cells from a single toxin warhead. Although the biochemical function of many of the effector domains is known (8), the additive or synergistic benefit of having all these enzymatic functions delivered on a single toxin has yet to be identified (9).…”

Accessory Toxins of Vibrio Pathogens and Their Role in Epithelial Disruption During Infection

“…However, in host cells the cytotoxicity of RTX toxins produces also apoptosis, although the mechanisms is not understood ( Wiles and Mulvey, 2013 ). The best characterized are the multifunctional-autoprocessing RTX (MARTX) toxins, a subgroup of very large RTX proteins (range from 3,500 to 5,300 aminoacid residues) with multiple activities and which constitute a combination of secreted toxins and multi-effector delivery systems ( Woida and Satchell, 2018 ). These proteins are encoded by V. cholerae (VcRtxA), V. vulnificus and other pathogens ( Lee et al, 2008 ).…”

Structural basis of inactivation of Ras and Rap1 small GTPases by Ras/Rap1-specific endopeptidase from the sepsis-causing pathogen Vibrio vulnificus

“…Once secreted, these toxins translocate their effector domains modularly into host cells and undergo autoproteolysis, resulting in the release of functionally discrete effectors in the cytosol ( 10 , 11 ). MARTX toxins are believed to form pores in the host cell plasma membrane via repeat-containing regions located at the N and C termini that facilitate effector module translocation, although how the repeat regions form pores remains unknown ( 10 – 12 ). Autoproteolysis essential for MARTX toxin function is mediated by a core element of the toxins, namely the cysteine protease domain that is allosterically activated by inositol hexakisphosphate exclusively present in the host cytosol ( 13 ).…”

“…Within host cells, different effectors display distinct cytopathicity or cytotoxicity, and the overall toxicity depends on the combined virulence of individual MARTX toxin effectors ( 12 , 14 ). Because pathogenic bacteria confer variation on the effector domain content of MARTX toxins by homologous recombination events, MARTX toxin-mediated translocation of novel effector domains emerges spontaneously ( 15 , 16 ).…”