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Human SIDT1 mediates dsRNA uptake via its phospholipase activity

Cell Research volume 34, pages 84–87 (2024)Cite this article

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Dear Editor,

Systemic RNA interference (RNAi) refers to post-transcriptional gene silencing that spreads throughout the organism and its progeny, which could be triggered by double-stranded (ds) RNA.1,2 Hunter and colleagues identified that a ubiquitously expressed putative transmembrane protein SID-1 (systemic RNAi defective-1) in Caenorhabditis elegans is required for systemic RNAi,3 via acting as a channel to passively transport extracellular dsRNA into cells.4,5 SIDT1 (SID-1 transmembrane family member 1) is a SID-1 homolog in humans. Previous reports showed that it could facilitate the cellular uptake of both short interfering RNAs and microRNAs (miRNA).6,7,8 Given a sequence identity of ~24%, SIDT1 might function in a way similar to nematode SID-1. However, the molecular mechanism of either SID-1-mediated RNAi or SIDT1-facilitated dsRNA uptake remains unknown.

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Fig. 1: Structures of human SIDT1 and its phospholipase activity-dependent dsRNA uptake.

Data availability

All relevant data are available from the authors and/or included in the manuscript or Supplementary information. The cryo-EM structures of wild-type SIDT1 complexed with PA and SIDT1E555Q have been deposited at PDB under the codes of 8JUL and 8JUN, respectively. The cryo-EM density maps of two structures have been deposited at the Electron Microscopy Data Bank under accession codes: EMD-36661 for PA-bound SIDT1, and EMD-36662 for SIDT1E555Q.

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Acknowledgements

We thank Dr. Yong-Xiang Gao for technical support on cryo-EM data collection at the Cryo-EM Center at the University of Science and Technology of China (USTC). This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB37020202) and Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYZD20220001).

Author information

Author notes

  1. These authors contributed equally: Cai-Rong Sun, Da Xu, Fengrui Yang.

Authors and Affiliations

  1. School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China

    Cai-Rong Sun, Da Xu, Yuxing Chen, Qiong Li & Cong-Zhao Zhou

  2. Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, Anhui, China

    Cai-Rong Sun, Da Xu, Yuxing Chen, Qiong Li & Cong-Zhao Zhou

  3. MOE Key Laboratory for Cellular Dynamics, University of Science and Technology of China, Hefei, Anhui, China

    Fengrui Yang & Xuebiao Yao

  4. School of Chemistry and Materials Science, National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, Anhui, China

    Zhuanghao Hou & Guangming Huang

  5. Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China

    Yuyao Luo & Ge Shan

  6. Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China

    Chen-Yu Zhang

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Contributions

C.Z.Z., Y.C. and Q.L. conceptualized and supervised the project. C.R.S., D.X. and Q.L. designed all the experiments. C.Y.Z. provides the plasmid encoding SIDT1. C.R.S. performed cloning, expression, purification and cryo-EM sample preparation. C.R.S. and D.X. preformed cryo-EM data collection, structure determination and model refinement. C.R.S. preformed phospholipase activity assays. Z.H. and G.H. performed mass spectrometry analyses. F.Y., X.Y., Y.L. and G.S. performed fluorescence experiments and data analyses. Q.L., C.R.S., C.Z.Z. and Y.C. wrote the manuscript.

Corresponding authors

Correspondence to Xuebiao Yao, Yuxing Chen, Qiong Li or Cong-Zhao Zhou.

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The authors declare no competing interests.

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Sun, CR., Xu, D., Yang, F. et al. Human SIDT1 mediates dsRNA uptake via its phospholipase activity. Cell Res 34, 84–87 (2024). https://doi.org/10.1038/s41422-023-00889-x

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