Hou Gaopeng, Beatty Wandy, Ren Lili, Ooi Yaw Shin, Son Juhee, Zhu Yinxing, Sheng Qingyu, Huang Wanyi, Li Dian, Liu Constin, Welsh Olivia L, Sutherland Danica M, Dermody Terence S, Shen Chen, Liu Jia, Sibley L David, Ding Siyuan
Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA.
Nat Commun. 2025 Apr 22;16(1):3756. doi: 10.1038/s41467-025-59090-w.
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.
对源自微生物或内源性来源的胞质双链（ds）DNA或dsRNA分子的感知会触发细胞内在的先天免疫，但同时识别胞质dsDNA和dsRNA的传感器鲜有报道。在此，我们发现全长人类SAMD9蛋白直接结合合成的或病毒的dsDNA或dsRNA。来自各种脊椎动物物种的SAMD9过表达会导致干扰素和促炎细胞因子的大量产生。相比之下，内源性SAMD9的缺失会损害多种细胞类型对胞质dsDNA和dsRNA刺激的干扰素反应，并增强致病性dsDNA和dsRNA病毒的感染性。缺乏人类SAMD9同源物Samd9l的小鼠表现出病毒载量增加以及轮状病毒和呼肠孤病毒感染的严重临床表现。轮状病毒编码的非结构蛋白1靶向SAMD9进行蛋白酶体降解。总体而言，我们的数据表明，SAMD9可能作为跨不同生命领域的胞质dsDNA和dsRNA的模式识别受体，并代表病毒先天免疫逃逸的潜在靶点。
