SAMD9 senses cytosolic double-stranded nucleic acids in epithelial and mesenchymal cells to induce antiviral immunity
Sensing of cytosolic, double-stranded (ds) DNA or dsRNA molecules derived from microbial or endogenous sources triggers cell-intrinsic innate immunity, but sensors recognizing both cytosolic dsDNA and dsRNA are sparsely reported. Here we find that full-length human SAMD9 protein directly binds to synthetic or viral dsDNA or dsRNA. Overexpression of SAMD9 from various vertebrate species leads to robust production of interferons and pro-inflammatory cytokines. By contrast, loss of endogenous SAMD9 impairs the interferon responses to cytosolic dsDNA and dsRNA stimulation in multiple cell types and enhances the infectivity of pathogenic dsDNA and dsRNA viruses. Mice lacking Samd9l, the human SAMD9 homolog, show increased viral load and severe clinical manifestations of rotavirus and reovirus infections. Rotavirus-encoded non-structural protein 1 targets SAMD9 for proteasomal degradation. Collectively, our data demonstrate that SAMD9 may serve as a pattern-recognition receptor for cytosolic dsDNA and dsRNA across different domains of life and represents a potential target of viral innate immune evasion.
Authors
- Qinsong Sheng
- Wanyi Huang (ORCID: https://orcid.org/0009-0006-3626-2135)
- Wandy L. Beatty (ORCID: https://orcid.org/0000-0003-0715-7361)
- Gaopeng Hou (ORCID: https://orcid.org/0000-0003-4753-9743)
- Siyuan Ding (ORCID: https://orcid.org/0000-0002-5338-260X)
- Chen Shen (ORCID: https://orcid.org/0000-0002-5439-7133)
- Terence S. Dermody (ORCID: https://orcid.org/0000-0003-1853-8741)
- Constin Liu
- L. David Sibley (ORCID: https://orcid.org/0000-0001-7110-0285)
- Juhee Son (ORCID: https://orcid.org/0000-0001-9605-7017)
- Danica M. Sutherland (ORCID: https://orcid.org/0000-0001-9328-4994)
- Yinxing Zhu (ORCID: https://orcid.org/0000-0002-6161-7819)
- Yaw Shin Ooi (ORCID: https://orcid.org/0000-0001-9014-1365)
- Jia Liu (ORCID: https://orcid.org/0000-0001-8424-7972)
- Olivia L. Welsh (ORCID: https://orcid.org/0000-0002-8039-7807)
- Dian Li (ORCID: https://orcid.org/0000-0002-5374-7314)
- Lili Ren (ORCID: https://orcid.org/0000-0001-6423-9625)
Institutions
- Nanjing Tech University (CN)
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
- VA Palo Alto Health Care System (US)
- Palo Alto Veterans Institute for Research (US)
- Duke-NUS Medical School (SG)
- Children's Hospital of Pittsburgh (US)
- University of Arkansas for Medical Sciences (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1038/s41467-025-59090-w
- Citations
- 13
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 10.37
Funders
- Institute of Clinical and Translational Sciences
- Alvin J. Siteman Cancer Center
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- Center for Cellular Imaging, Washington University
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences