Schlafen 11 triggers innate immune responses through its ribonuclease activity upon detection of single-stranded DNA

IF 17.6 1区 医学 Q1 IMMUNOLOGY Science Immunology Pub Date : 2024-06-14 DOI:10.1126/sciimmunol.adj5465
Peng Zhang, Xiaoqing Hu, Zekun Li, Qian Liu, Lele Liu, Yingying Jin, Sizhe Liu, Xiang Zhao, Jianqiao Wang, Delong Hao, Houzao Chen, Depei Liu
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Abstract

Nucleic acids are major structures detected by the innate immune system. Although intracellular single-stranded DNA (ssDNA) accumulates during pathogen infection or disease, it remains unclear whether and how intracellular ssDNA stimulates the innate immune system. Here, we report that intracellular ssDNA triggers cytokine expression and cell death in a CGT motif–dependent manner. We identified Schlafen 11 (SLFN11) as an ssDNA-activated RNase, which is essential for the innate immune responses induced by intracellular ssDNA and adeno-associated virus infection. We found that SLFN11 directly binds ssDNA containing CGT motifs through its carboxyl-terminal domain, translocates to the cytoplasm upon ssDNA recognition, and triggers innate immune responses through its amino-terminal ribonuclease activity that cleaves transfer RNA (tRNA). Mice deficient in Slfn9, a mouse homolog of SLFN11, exhibited resistance to CGT ssDNA–induced inflammation, acute hepatitis, and septic shock. This study identifies CGT ssDNA and SLFN11/9 as a class of immunostimulatory nucleic acids and pattern recognition receptors, respectively, and conceptually couples DNA immune sensing to controlled RNase activation and tRNA cleavage.
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Schlafen 11 在检测到单链 DNA 时通过核糖核酸酶活性触发先天性免疫反应。
核酸是先天性免疫系统检测到的主要结构。虽然细胞内单链 DNA(ssDNA)会在病原体感染或疾病期间积累,但细胞内ssDNA是否以及如何刺激先天性免疫系统仍不清楚。在这里,我们报告了细胞内 ssDNA 以 CGT 基序依赖的方式触发细胞因子的表达和细胞死亡。我们发现Schlafen 11(SLFN11)是一种ssDNA激活的RNase,它对于细胞内ssDNA和腺相关病毒感染诱导的先天性免疫反应至关重要。我们发现,SLFN11通过其羧基末端结构域直接与含有CGT基序的ssDNA结合,在识别到ssDNA后转运到细胞质,并通过其氨基末端的核糖核酸酶活性裂解转运RNA(tRNA),触发先天性免疫反应。缺乏Slfn9(SLFN11的小鼠同源物)的小鼠对CGT ssDNA诱导的炎症、急性肝炎和脓毒性休克有抵抗力。这项研究将 CGT ssDNA 和 SLFN11/9 分别确定为一类免疫刺激核酸和模式识别受体,并从概念上将 DNA 免疫感应与受控 RNase 激活和 tRNA 裂解联系起来。
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来源期刊
Science Immunology
Science Immunology Immunology and Microbiology-Immunology
CiteScore
32.90
自引率
2.00%
发文量
183
期刊介绍: Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.
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