New Findings on the Detection of Single-Stranded DNA by the Human Immune System: The Role of Schlafen 11 in Innate Immune Response

Research Background

In the innate immune system, pattern recognition receptors (PRRs) play a crucial role. They initiate an immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). For a long time, researchers have found that the accumulation of bacterial or viral single-stranded DNA (ssDNA) within cells can trigger an immune response, but the mechanism of how ssDNA is recognized and responded to remains unclear.

A research team led by Peng Zhang, Xiaoqing Hu, Zekun Li, and others has published new evidence on the critical role of Schlafen 11 (Slfn11) in ssDNA detection and the initiation of immune response. The team demonstrated that Slfn11, as a ribonuclease activated by ssDNA, is essential for the immune system’s response. Specifically, the study showed the mechanism by which Slfn11 recognizes ssDNA containing the CGT motif and its role in ssDNA sensing.

Research Source

This study was conducted by Peng Zhang and others, from the Department of Biochemistry and Molecular Biology at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. The findings were published in “Science Immunology,” document number eadj5465, on June 14, 2024.

Research Details

The research team undertook extensive experiments involving the screening of ssDNA libraries, functional analysis of Slfn11, and animal model studies. By screening a library of short ssDNA, researchers identified the smallest ssDNA mimic that activates the immune response, which is a fragment containing the CGT motif. Using CRISPR-Cas9 screening and gene editing technologies, the researchers further validated the role of Slfn11 as an ssDNA sensor and found that its C-terminal domain binds to the CGT motif in ssDNA, while the N-terminal ribonuclease activity is crucial for triggering the immune response.

Research Results

The experimental results showed that ssDNA containing the CGT motif significantly activated cytokine expression and cell death pathways, and this activation process depended on the endogenous expression of Slfn11. When animal models lacked the homologous gene of Slfn11, Slfn9, they showed resistance to CGT ssDNA-mediated inflammation, acute hepatitis, and septic shock, highlighting the importance of Slfn11/9 in endogenous ssDNA sensing.

Research Significance

This study provides new insights into how the immune system responds to pathogen ssDNA and the accumulation of endogenous ssDNA, potentially having clinical significance for future developments in the fields of inflammation, disease, especially autoimmune diseases, and cancer therapy. The new immune response pathway identified in the study also offers a theoretical foundation for developing a new generation of immunotherapy strategies.

Research Highlights

• Identified the CGT motif as the key ssDNA sequence for activating Slfn11.
• Revealed the dual function of Slfn11: ssDNA binding and regulation of ribonuclease activity.
• Provided molecular mechanisms of ssDNA-triggered immune response.
• Established the connection between tRNA cleavage following Slfn11 activation and the initiation of immune response.

Other Information

In addition to the main research findings, the study also provided insights into the structure of the Slfn11 protein, which may help further understand its interaction with ssDNA and its transport mechanisms within cells.

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This report summarizes the significant research by Peng Zhang and others on the role of Slfn11 in ssDNA sensing and innate immune response. This work not only fills the previous gap in understanding the mechanism of ssDNA sensing but also provides new perspectives for future study of DNA-induced immune responses, offering significant academic reference value for researchers and clinicians alike.