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Vibrio MARTX toxin processing and degradation of cellular Rab GTPases by the cytotoxic effector Makes Caterpillars Floppy.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jun 18; Vol. 121 (25), pp. e2316143121. Date of Electronic Publication: 2024 Jun 11. - Publication Year :
- 2024
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Abstract
- Vibrio vulnificus causes life-threatening wound and gastrointestinal infections, mediated primarily by the production of a Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX) toxin. The most commonly present MARTX effector domain, the Makes Caterpillars Floppy-like (MCF) toxin, is a cysteine protease stimulated by host adenosine diphosphate (ADP) ribosylation factors (ARFs) to autoprocess. Here, we show processed MCF then binds and cleaves host Ra s-related proteins in b rain (Rab) guanosine triphosphatases within their C-terminal tails resulting in Rab degradation. We demonstrate MCF binds Rabs at the same interface occupied by ARFs. Moreover, we show MCF preferentially binds to ARF1 prior to autoprocessing and is active to cleave Rabs only subsequent to autoprocessing. We then use structure prediction algorithms to demonstrate that structural composition, rather than sequence, determines Rab target specificity. We further determine a crystal structure of aMCF as a swapped dimer, revealing an alternative conformation we suggest represents the open, activated state of MCF with reorganized active site residues. The cleavage of Rabs results in Rab1B dispersal within cells and loss of Rab1B density in the intestinal tissue of infected mice. Collectively, our work describes an extracellular bacterial mechanism whereby MCF is activated by ARFs and subsequently induces the degradation of another small host guanosine triphosphatase (GTPase), Rabs, to drive organelle damage, cell death, and promote pathogenesis of these rapidly fatal infections.<br />Competing Interests: Competing interests statement:The authors declare no competing interest.
- Subjects :
- Animals
Female
Humans
Mice
ADP-Ribosylation Factors metabolism
HEK293 Cells
Mice, Inbred ICR
Proteolysis
Vibrio Infections microbiology
Vibrio Infections metabolism
Bacterial Toxins metabolism
Bacterial Toxins chemistry
rab GTP-Binding Proteins metabolism
Vibrio vulnificus metabolism
Vibrio vulnificus pathogenicity
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 121
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 38861595
- Full Text :
- https://doi.org/10.1073/pnas.2316143121