GBP1 recruitment to actin-rich pedestals of extracellular Gram-negative bacteria promotes pyroptosis
The IFNγ-induced GTPase guanylate-binding protein 1 (GBP1) binds to lipopolysaccharide (LPS) on cytosolic gram-negative bacteria and promotes pyroptosis via the recruitment and activation of caspase-4 on the bacterial outer membrane. Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC, respectively) are extracellular pathogens that adhere to host cells and stimulate dense actin polymerisation underneath their attachment sites, generating structures described as actin-rich pedestals. Here, we show that GBP1 traffics to actin-rich pedestals in human cells infected with EPEC or EHEC in vitro and mouse colonocytes infected with the EPEC-like murine pathogen Citrobacter rodentium in vivo. GBP1 promotes caspase-4 recruitment to actin-rich pedestals, leading to pyroptosis and IL-18 release. GBP1 mutants defective in LPS coatomer formation also localise to EPEC pedestals. A novel assay that mimics pathogenic effector activity reveals GBP1 recruitment to sterile actin polymerisation sites. We conclude that cytosolic GBP1 is mobilised to sites of pathogen-induced actin remodelling independently of LPS. Our study establishes that GBP1 not only operates as a pattern-recognition receptor but also orchestrates effector-triggered immunity against pathogens that hijack the actin cytoskeleton.
Authors
- Edward W. Tate (ORCID: https://orcid.org/0000-0003-2213-5814)
- Tamás Korcsmáros (ORCID: https://orcid.org/0000-0003-1717-996X)
- Qiyun Zhong (ORCID: https://orcid.org/0000-0001-7053-9640)
- Sandhya Srikant Visweswariah (ORCID: https://orcid.org/0000-0003-2786-7344)
- Gad M. Frankel (ORCID: https://orcid.org/0000-0002-0046-1363)
- Avinash R. Shenoy (ORCID: https://orcid.org/0000-0001-6228-9303)
- Wouter W. Kallemeijn (ORCID: https://orcid.org/0000-0002-3660-2930)
- Daniel J. Bennison (ORCID: https://orcid.org/0000-0001-9026-9262)
- Arthur M. Talman (ORCID: https://orcid.org/0000-0003-2584-3672)
- Marianne Guenot
- Eva‐Maria Frickel (ORCID: https://orcid.org/0000-0002-9515-3442)
- Dharitri CHAUDHURİ
- Dimple Dixit
- Priyanka Paul Biswas (ORCID: https://orcid.org/0000-0003-1932-2352)
- John P. Thomas (ORCID: https://orcid.org/0000-0001-7495-4630)
- Ishaan Chaudhary
- Miyu Stephenson
- Justin Chun Ngai Wong
- Ayush Punwatkar
- Sandra Koigi
- Diana Papp
Institutions
- University of Geneva (CH)
- Centre National de la Recherche Scientifique (FR)
- Indian Institute of Science Education and Research Pune (IN)
- Université de Montpellier (FR)
- The Francis Crick Institute (GB)
- Hammersmith Hospital (GB)
- Maladies Infectieuses et Vecteurs: Écologie, Génétique, Évolution et Contrôle (FR)
- NIHR Imperial Biomedical Research Centre (GB)
- Institut de Recherche pour le Développement (FR)
- Imperial College London (GB)
- Indian Institute of Science Bangalore (IN)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-06-09
- DOI
- https://doi.org/10.1038/s44318-026-00830-z
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Cancer Research UK
- Commonwealth Scholarship Commission
- National Institutes of Health
- Medical Research Council
- NIHR Imperial Biomedical Research Centre
- Cancer Research UK Therapeutic Discovery Laboratories