Schlafen 11 triggers innate immune responses through its ribonuclease activity upon detection of single-stranded DNA
Peng Zhang 1, Xiaoqing Hu 1, Zekun Li 1,
Qian Liu 1, Lele Liu 1, Yingying Jin 1, Sizhe Liu 1, Xiang Zhao 1, Jianqiao
Wang 1, Delong Hao 1, Houzao Chen 1, Depei Liu 1 2
Sci Immunol. 2024 Jun 14;9(96):eadj5465.
doi: 10.1126/sciimmunol.adj5465.
PMID: 38875319
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.