Luz Saavedra Sanchez
Coers Lab
Microbial Pathogenesis and Host Response 2025 meeting, Cold Spring Harbor, New York
September 8-25, 2025
Abstract
The Shigella flexneri effector IpaH1.4 degrades the E3 ligase RNF213 and protects Shigella against ubiquitylation Ubiquitylation is a conserved pathway that is required for the detection and subsequent clearance of infectious bacteria, viruses, and fungi. Given that ubiquitylation is a clear threat to cytosolic pathogens, cytosolic bacteria like Burkholderia are resistant to ubiquitylation. We therefore asked whether the professional cytosolic pathogen and causing agent of bacillary dysentery, Shigella flexneri could also escape cytosolic ubiquitylation. By using bacterial genetics and cell biology approaches, we uncovered for the first time how Shigella counteracts the host ubiquitylation machinery. Mechanistically, we found that Shigella secretes the virulence factor IpaH1.4 which triggers the proteasomal degradation of RNF213, an E3 ligase responsible for ubiquitylating multiple pathogens. Indeed, S. flexneri mutants lacking IpaH1.4 are coated with ubiquitin and RNF213 in the host cytosol. Moreover, the complementation with IpaH1.4 drastically reduced the ubiquitin and RNF213 coat on S.flexneri, while the complementation with the catalytically inactive IpaH1.4 reversed the phenotype. We also discovered that the conjugation of linear and lysine-linked ubiquitin to bacteria is solely dependent on RNF213 and independent of the E3 ligase LUBAC. Strikingly, we found that ubiquitylation of S. flexneri is insufficient to restrict S.flexneri bacterial growth. This finding suggests that S. flexneri uses additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. As a whole, we have discovered the first direct inhibitor of RNF213-driven immunity against S.flexneri.