Dataset Information

Vibrio MARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy.

ABSTRACT: Vibrio vulnificus causes life threatening infections dependent upon the effectors released from the Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin. The Makes Caterpillars Floppy-like (MCF) cysteine protease effector is activated by host ADP ribosylation factors (ARFs), although the targets of processing activity were unknown. In this study we show MCF binds Ras-related proteins in brain (Rab) GTPases at the same interface occupied by ARFs and then cleaves and/or degrades 24 distinct members of the Rab GTPases family. The cleavage occurs in the C-terminal tails of Rabs. We determine the crystal structure of MCF as a swapped dimer revealing the open, activated state of MCF and then use structure prediction algorithms to show that structural composition, rather than sequence or localization, determine Rabs selected as MCF proteolytic targets. Once cleaved, Rabs become dispersed in cells to drive organelle damage and cell death to promote pathogenesis of these rapidly fatal infections.

SUBMITTER: Herrera A

PROVIDER: S-EPMC10153396 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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<i>Vibrio</i> MARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy.

Herrera Alfa A Packer Megan M MM Rosas-Lemus Monica M Minasov George G Brummel John H JH Satchell Karla J F KJF

bioRxiv : the preprint server for biology 20230512

<i>Vibrio vulnificus</i> causes life threatening infections dependent upon the effectors released from the Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin. The Makes Caterpillars Floppy-like (MCF) cysteine protease effector is activated by host ADP ribosylation factors (ARFs), although the targets of processing activity were unknown. In this study we show MCF binds Ras-related proteins in brain (Rab) GTPases at the same interface occupied by ARFs and then cleaves and/or degrades 24 ...[more]

PMID: 37131655

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Project description:Vibrio vulnificus is an environmental organism that causes septic human infections characterized by high morbidity and mortality. The annual incidence and global distribution of this pathogen are increasing as ocean waters warm. Clinical strains exhibit variations in the primary virulence toxin, suggesting a potential for the emergence of new strains with altered virulence properties. A clonal outbreak of tilapia-associated wound infections in Israel serves as a natural experiment for the sudden emergence of a new V. vulnificus strain. The effector domain content of the multifunctional autoprocessing RTX (MARTX) toxin of the outbreak-associated biotype 3 (BT3) strains was previously shown to harbor a modification generated by recombination. The modification introduced an actin-induced adenylate cyclase effector domain (ExoY) and an effector domain that disrupts the Golgi organelle (DmX). Here, we report that the exchange of these effector domains for a putative progenitor biotype 1 toxin arrangement produces a toxin that slows the lysis kinetics of targeted epithelial cells but increases cellular rounding phenotypes in response to bacteria. In addition, replacing the biotype 3 toxin variant with the putative progenitor biotype 1 variant renders the resulting strain significantly more virulent in mice. This suggests that the exchange of MARTX effector domains during the emergence of BT3 generated a toxin with reduced toxin potency, resulting in decreased virulence of this outbreak-associated strain. We posit that selection for reduced virulence may serve as a route for this lethal infectious agent to enter the human food chain by allowing it to persist in natural hosts. IMPORTANCEVibrio vulnificus is a serious infection linked to climate change. The virulence capacity of these bacteria can vary by gene exchange, resulting in new variants of the primary virulence toxin. In this study, we tested whether the emergence of an epidemic strain of V. vulnificus with a novel toxin variant correlated with a change in virulence. We found that restoring the biotype 3 toxin variant to the putative progenitor-type toxin resulted in dramatically increased virulence, revealing that the emergence of the biotype 3 strain could be linked to virulence reduction. This reduced virulence, previously found also in the biotype 1 strain, suggests that reduced virulence may stimulate outbreaks, as strains have greater capacity to enter the human food chain through reduced impact to environmental hosts.

Dataset Information

Vibrio MARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy.

Publications

<i>Vibrio</i> MARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy.

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