SAMD9 senses cytosolic double-stranded nucleic acids in epithelial and mesenchymal cells to induce antiviral immunity

Gaopeng Hou, Wandy Beatty, Lili Ren, Yaw Shin Ooi, Juhee Son, Yinxing Zhu, Qingyu Sheng, Wanyi Huang, Dian Li, Constin Liu, Olivia L. Welsh, Danica M. Sutherland, Terence S. Dermody, Chen Shen, Jia Liu, L. David Sibley and Siyuan Ding ()
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Gaopeng Hou: Washington University School of Medicine in St. Louis
Wandy Beatty: Washington University School of Medicine in St. Louis
Lili Ren: Stanford University
Yaw Shin Ooi: Stanford University
Juhee Son: Washington University School of Medicine in St. Louis
Yinxing Zhu: Washington University School of Medicine in St. Louis
Qingyu Sheng: Washington University School of Medicine in St. Louis
Wanyi Huang: Washington University School of Medicine in St. Louis
Dian Li: Washington University in St. Louis
Constin Liu: Washington University School of Medicine in St. Louis
Olivia L. Welsh: University of Pittsburgh School of Medicine
Danica M. Sutherland: University of Pittsburgh School of Medicine
Terence S. Dermody: University of Pittsburgh School of Medicine
Chen Shen: Washington University School of Medicine in St. Louis
Jia Liu: University of Arkansas for Medical Sciences
L. David Sibley: Washington University School of Medicine in St. Louis
Siyuan Ding: Washington University School of Medicine in St. Louis

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59090-w

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