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Structural insights into double-stranded RNA recognition and transport by SID-1

文献类型： 外文期刊

作者： Zhang, Jiangtao 1 ; Zhan, Chunhua 1 ; Fan, Junping 3 ; Wu, Dian 1 ; Zhang, Ruixue 4 ; Wu, Di 2 ; Chen, Xinyao 2 ; Lu, Ying 2 ; Li, Ming 2 ; Lin, Min 6 ; Gong, Jianke 1 ; Jiang, Daohua 2 ;

作者机构： 1.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Key Lab Mol Biophys MOE, Wuhan, Hubei, Peoples R China

2.Chinese Acad Sci, Inst Phys, Lab Soft Matter Phys, Beijing, Peoples R China

3.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol,State Key Lab Nat &, Beijing, Peoples R China

4.Chinese Acad Agr Sci, Biotechnol Res Inst, Key Lab Agr Microbiome MARA, Beijing, Peoples R China

5.Univ Chinese Acad Sci, Beijing, Peoples R China

6.Henan Univ Technol, Food Lab Zhongyuan, Zhengzhou 450001, Henan, Peoples R China

期刊名称：NATURE STRUCTURAL & MOLECULAR BIOLOGY （ 影响因子：16.8； 五年影响因子：14.5 ）

ISSN： 1545-9993

年卷期： 2024 年

页码：

收录情况： SCI

摘要： RNA uptake by cells is critical for RNA-mediated gene interference (RNAi) and RNA-based therapeutics. In Caenorhabditis elegans, RNAi is systemic as a result of SID-1-mediated double-stranded RNA (dsRNA) across cells. Despite the functional importance, the underlying mechanisms of dsRNA internalization by SID-1 remain elusive. Here we describe cryogenic electron microscopy structures of SID-1, SID-1-dsRNA complex and human SID-1 homologs SIDT1 and SIDT2, elucidating the structural basis of dsRNA recognition and import by SID-1. The homodimeric SID-1 homologs share conserved architecture, but only SID-1 possesses the molecular determinants within its extracellular domains for distinguishing dsRNA from single-stranded RNA and DNA. We show that the removal of the long intracellular loop between transmembrane helix 1 and 2 attenuates dsRNA uptake and systemic RNAi in vivo, suggesting a possible endocytic mechanism of SID-1-mediated dsRNA internalization. Our study provides mechanistic insights into dsRNA internalization by SID-1, which may facilitate the development of dsRNA applications based on SID-1. In C. elegans, systemic RNAi is initiated by SID-1-mediated dsRNA internalization. Here the authors present cryo-EM structures of SID-1 homologs and the SID-1-dsRNA complex, elucidating the structural basis for dsRNA recognition and uptake by SID-1.

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