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

• 成果类型: Article
• 署名作者: Herrera, Alfa; Packer, Megan M.; Lemus, Monica Rosas-; Minasov, George; Chen, Jiexi; Brumell, John H.; Satchell, Karla J. F.
• 署名单位: Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of New Mexico
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11152
• DOI: 10.1073/pnas.2316143121
• 发表日期: 2024-06-18
• 关键词: phagosome maturation; domain; proteins; phosphorylation; PATHWAY; targets; FAMILY; golgi

摘要

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 Ras- related proteins in brain (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.