Septin binding restricts Shigella growth and triggers intracellular tolerance
Pathogen survival relies on their ability to adapt to changing environments, yet how intracellular bacteria tolerate cell-autonomous immunity remains unclear. Septins assemble into cage-like structures around cytoplasmic Shigella targeted by autophagy, but their antibacterial activity was unknown. Using advanced microscopy and cell-free reconstitution, we show that septins polymerize into circumferentially oriented filaments that inhibit bacterial growth. RNA-sequencing reveals that septin binding to Shigella upregulates type III secretion system (T3SS) effectors and triggers a stress response. Underlying this, septin-bound Shigella possess hyperpolarized membranes, but without lethally damaged cell envelope. We show that exposure to septin binding enhances the impact of the cell envelope-targeting antibiotic polymyxin B. During infection, T3SS effector OspC1 prevents septin recruitment, while stress-response regulator cspC protects against septin-mediated changes to membrane potential. Hence, septin binding is intrinsically antibacterial and is sensed by Shigella as a danger signal to promote mechanisms of intracellular tolerance.
Authors
- Serge Mostowy (ORCID: https://orcid.org/0000-0002-7286-6503)
- Teresa Cortes (ORCID: https://orcid.org/0000-0002-5746-3300)
- Suliana Manley (ORCID: https://orcid.org/0000-0002-4755-4778)
- Ivo Gomperts Boneca (ORCID: https://orcid.org/0000-0001-8122-509X)
- Gizem Özbaykal Güler (ORCID: https://orcid.org/0000-0002-9115-7120)
- Rajdeep Das (ORCID: https://orcid.org/0000-0001-8127-9055)
- Richard H. Wheeler (ORCID: https://orcid.org/0000-0002-9249-2377)
- Dominik Brokatzky (ORCID: https://orcid.org/0000-0001-6304-3292)
- Chen Zhang (ORCID: https://orcid.org/0000-0003-1468-2906)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Consejo Superior de Investigaciones Científicas (ES)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- London School of Hygiene & Tropical Medicine (GB)
- Instituto de Biomedicina de Valencia (ES)
- Microbiologie Intégrative et Moléculaire (FR)
- École Polytechnique Fédérale de Lausanne (CH)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-10-27
- DOI
- https://doi.org/10.1073/pnas.2529720123
- Primary Topic
- Escherichia coli research studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- European Commission
- Human Frontier Science Program
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Ministerio de Ciencia e Innovación
- Horizon 2020 Framework Programme
- European Research Council
- Instituto de Salud Carlos III
- European Regional Development Fund
- Agencia Estatal de Investigación
- Labex Immuno-Oncology
- NextGenerationEU