Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion
Diverse pathogen-encoded virulence factors disable apoptosis, pyroptosis or necroptosis, the host cell death programs that remove infected cells<sup>1</sup>. In the intestine, the extrusion of infected cells into the lumen for elimination provides an additional layer of host defence, but no virulence mechanisms that target the cytoskeletal changes required are known<sup>2</sup>. Here we show that the Escherichia coli ubiquitin ligase NleL is an inhibitor of intestinal epithelial cell (IEC) extrusion, targeting caspase-4, ROCK1 and ROCK2 for proteasomal degradation. Genetic deletion of Rock1 and Rock2 from cultured IECs diminished inflammasome-induced IEC extrusion. Moreover, mice with Rock1- and Rock2-deficient IECs were less effective than wild-type mice at constraining the numbers of Citrobacter rodentium in the colon. Notably, NleL-deficient C. rodentium triggered more IEC extrusion than did wild-type C. rodentium, resulting in diminished colonization of the colon in infected mice. Our work highlights a host-pathogen arms race focused on dynamic regulation of the host epithelial barrier.
Authors
- Man‐Wah Tan (ORCID: https://orcid.org/0000-0002-7748-212X)
- R. Peterson
- Isabella Rauch (ORCID: https://orcid.org/0000-0003-1897-5693)
- Hua Zhang (ORCID: https://orcid.org/0000-0001-5936-7876)
- Eric M. Kofoed (ORCID: https://orcid.org/0000-0002-1779-4914)
- Elizabeth Skippington
- Tommy K. Cheung
- Nobuhiko Kayagaki (ORCID: https://orcid.org/0000-0001-8129-1740)
- Marin Miner (ORCID: https://orcid.org/0000-0002-3215-1490)
- W. P. Scott (ORCID: https://orcid.org/0000-0002-1473-4377)
- Giovanni Luchetti (ORCID: https://orcid.org/0000-0002-7684-9612)
- Rohit Reja (ORCID: https://orcid.org/0000-0002-2254-3968)
- Angel G. Jimenez (ORCID: https://orcid.org/0000-0002-9949-3874)
- Christopher M. Rose (ORCID: https://orcid.org/0000-0002-7502-3368)
- Kim Newton (ORCID: https://orcid.org/0000-0002-4197-0340)
- Vishva M. Dixit (ORCID: https://orcid.org/0000-0001-6983-0326)
- Praveen Krishnamoorthy
- Yuxin Liang (ORCID: https://orcid.org/0000-0002-1143-423X)
Institutions
- Oregon Health & Science University (US)
- Gene Therapy Laboratory (FR)
- Genomic Health (United States) (US)
Publication Details
- Journal
- Nature
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1038/s41586-025-09645-0
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 0.00