2. Academic Validation
  3. Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion

Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion

  • Nature. 2025 Oct 22. doi: 10.1038/s41586-025-09645-0.
Giovanni Luchetti 1,  Marin V Miner 2,  Rachael M Peterson 2,  William P Scott 2,  Praveen Krishnamoorthy 3,  Eric M Kofoed 4,  Angel G Jimenez 4,  Hua Zhang 5,  Man Wah Tan 4,  Rohit Reja 6 7,  Tommy K Cheung 8,  Elizabeth Skippington 9,  Yuxin Liang 8,  Christopher M Rose 8,  Nobuhiko Kayagaki 6,  Kim Newton 6,  Isabella Rauch 10,  Vishva M Dixit 11
Affiliations

Affiliations

  • 1 Department of Discovery Oncology, Genentech, South San Francisco, CA, USA. luchettg@gene.com.
  • 2 Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA.
  • 3 Department of Pathology, Genentech, South San Francisco, CA, USA.
  • 4 Department of Immunology and Infectious Diseases, Genentech, South San Francisco, CA, USA.
  • 5 Department of Translational Immunology, Genentech, South San Francisco, CA, USA.
  • 6 Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
  • 7 Department of Oncology Bioinformatics, Genentech, South San Francisco, CA, USA.
  • 8 Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA.
  • 9 Department of OMNI Bioinformatics, Genentech, South San Francisco, CA, USA.
  • 10 Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA. rauchi@ohsu.edu.
  • 11 Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. dixit@gene.com.
PMID: 41125892 DOI: 10.1038/s41586-025-09645-0
Abstract

Diverse pathogen-encoded virulence factors disable Apoptosis, Pyroptosis or Necroptosis, the host cell death programs that remove infected cells1. 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 known2. 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.

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