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PreprintCited by 3Bacteriophages and microbial interactionsInvertebrate Immune Response MechanismsCRISPR and Genetic Engineering

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A phage-encoded sponge protein suppresses TIR-Caspase immune signaling

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Han, Wenyuan, Chen, Yu, Wei, Linlin, Han, Zhenhao, Zhao, Ruiliang, Zeng, Zhifeng, Liu, Yanqiu, Zhang, Piaoran, Tan, Keyi, Fan, Yue, Sheng, Long, Wang, Hao, Pinilla-Redondo, Rafael, Feng, Yue·2025·Nature Communications
DOI 10.21203/rs.3.rs-7669871/v1PMC PMC13243611

Preprint — published as 10.1038/s41467-026-71527-4

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Abstract

Triggering immune response through generation of signal molecules is a common immune strategy across all domains of life. In the bacterial type IV Thoeris anti-phage system, a Toll/interleukin-1 receptor (TIR)-domain protein produces N7-cADPR as the immune signal to activate a Caspase-like effector. Here, we identified an inhibitor of type IV Thoeris through a phage mating assay that allows a sensitive phage to acquire anti-defense genes from related resistant phages. The inhibitor (hereafter TadIV-1) functions as a sponge that sequesters the N7-cADPR signal to inhibit Caspase activation. Structural analyses of TadIV-1 indicate a distinctive signal binding mechanism, wherein the binding pocket comprises its N-terminal flexible loop. In addition, phages lacking TadIV-1 can escape type IV Thoeris sensing through mutation in the capsid vertex protein. Collectively, this work expands the phage anti-defense arsenal with an unprecedented immune signal sequestration mechanism and provides insights into phage invasion recognition mechanism of type IV Thoeris.

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Metadata

Authors
Han, W., Chen, Y., Wei, L., Han, Z., Zhao, R., Zeng, Z., Liu, Y., Zhang, P., Tan, K., Fan, Y., Sheng, L., Wang, H., Pinilla-Redondo, R., & Feng, Y.
Affiliations
  • Huazhong Agricultural University (CN)
  • Beijing University of Chemical Technology (CN)
  • University of Copenhagen (DK)
  • National University of Singapore (SG)
  • Army Medical University (CN)
  • University of Copenhagen
Corresponding author
  • Han, Wenyuan
  • Feng, Yue
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-10-08
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-7669871/v1
PMC
PMC13243611
OpenAlex
W7153892657
Cited by
3
References
1
Citations by year
2026: 3
FWCI
10.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Villum Fonden (VIL60763)
  • National Natural Science Foundation of China (32171274, 2022YFA0912200, 32270099, 31970545, BL19U1)
  • Tsinghua University
  • China Scholarship Council
  • Huazhong Agricultural University
  • National Key Research and Development Program of China (2022YFA0912200)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
  • Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords
TIR domain proteins, bacterial innate immunity, phage-bacteria interactions
MeSH terms
Bacterial Proteins, Bacteriophages, Viral Proteins, Signal Transduction, Receptors, Interleukin-1, Caspases

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