Systematic identification of Salmonella T6SS effectors uncovers diverse new families and lipid-targeting activities
Open accessPublished version of a preprint
Abstract
Bacterial warfare is a widespread phenomenon in which bacteria deploy toxins to inhibit or kill competitors. These toxins disrupt essential cellular processes, and their diversification is driven by an evolutionary arms race involving toxin and immunity gene acquisition. Here, we used in-silico approaches to analyze genomes from the 10k Salmonella Project and identify effectors secreted via the Type VI Secretion System (T6SS). We uncovered 128 candidates distributed across diverse Salmonella serovars and other bacterial species. Among them, Tox-Act1 was selected for in-depth characterization. Tox-Act1 contains a permuted NlpC/P60 papain-like catalytic core typical of lipid-targeting enzymes. Evolutionary analysis revealed its relationship with acyltransferases. Biochemical assays and lipidomics of intoxicated cells showed that Tox-Act1 acts as a phospholipase, cleaving phosphatidylglycerol and phosphatidylethanolamine. We further demonstrate that Tox-Act1 is secreted in a T6SS-dependent manner and provides a competitive advantage during mouse gut colonization. This study broadens our understanding of toxin domain diversity and provides the first direct characterization of a lipid-targeting NlpC/P60 toxin domain.
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- Authors
- Nicastro, G. G., Sibinelli-Sousa, S., Hespanhol, J. T., Santos, T. W. C., Munoz, J. P., Santos, R. S., Perez-Sepulveda, B. M., Miyamoto, S., Aravind, L., de Souza, R. F., & Bayer-Santos, E.
- Affiliations
- National Institutes of Health (US)
- The University of Texas at Austin (US)
- Universidade de São Paulo (BR)
- University of Liverpool (GB)
- ORCID
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2026-03-17
- Volume
- 24
- Issue
- 3
- Pages
- e3003680
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC11996579
- OpenAlex
- W7137868969
- Cited by
- 9
- References
- 7
- Citations by year
- 2026: 6 · 2025: 3
- FWCI
- 18.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2017-02178-2, 2013/07937-8, 2016/09047-8, 2021/10577-0)
- Coordenação de Aperfeiçoamento de Pessoal de NÃvel Superior (88887.823029/2023-00)
- College of Natural Sciences, University of Texas at Austin
- Oak Ridge Institute for Science and Education (DE-SC0014664)
- U.S. National Library of Medicine (ZIA LM594244)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Keywords
- Salmonella, type VI secretion system, T6SS effectors, phospholipase activity, phosphatidylglycerol, phosphatidylethanolamine, bacterial toxins, immunity genes, acyltransferase, intestinal colonization, bacterial competition
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