SAMD9 senses cytosolic double-stranded nucleic acids in epithelial and mesenchymal cells to induce antiviral immunity
Gaopeng Hou, Wandy L. 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, Siyuan Ding
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. Sensing of cytosolic RNA or DNA can lead to innate responses, but little information is available for RNA/DNA dual sensors. Here the authors find SAMD9 as a potential dual sensor linked to pro-inflammatory responses, interferon induction and resistance to viral infection, as evidenced by in vitro overexpression and in vivo knockout mouse data.