Zika virus RNA structure controls its unique neurotropism by bipartite binding to Musashi-1

Xiang Chen, Yan Wang, Zhonghe Xu, Meng-Li Cheng, Qing-Qing Ma, Rui-Ting Li, Zheng-Jian Wang, Hui Zhao, Xiaobing Zuo, Xiao-Feng Li, Xianyang Fang () and Cheng-Feng Qin ()
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Xiang Chen: Beijing Institute of Microbiology and Epidemiology, AMMS
Yan Wang: Tsinghua University
Zhonghe Xu: Tsinghua University
Meng-Li Cheng: Beijing Institute of Microbiology and Epidemiology, AMMS
Qing-Qing Ma: Beijing Institute of Microbiology and Epidemiology, AMMS
Rui-Ting Li: Beijing Institute of Microbiology and Epidemiology, AMMS
Zheng-Jian Wang: Beijing Institute of Microbiology and Epidemiology, AMMS
Hui Zhao: Beijing Institute of Microbiology and Epidemiology, AMMS
Xiaobing Zuo: X-ray Science Division, Argonne National Laboratory
Xiao-Feng Li: Beijing Institute of Microbiology and Epidemiology, AMMS
Xianyang Fang: Tsinghua University
Cheng-Feng Qin: Beijing Institute of Microbiology and Epidemiology, AMMS

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Human RNA binding protein Musashi-1 (MSI1) plays a critical role in neural progenitor cells (NPCs) by binding to various host RNA transcripts. The canonical MSI1 binding site (MBS), A/GU(1-3)AG single-strand motif, is present in many RNA virus genomes, but only Zika virus (ZIKV) genome has been demonstrated to bind MSI1. Herein, we identified the AUAG motif and the AGAA tetraloop in the Xrn1-resistant RNA 2 (xrRNA2) as the canonical and non-canonical MBS, respectively, and both are crucial for ZIKV neurotropism. More importantly, the unique AGNN-type tetraloop is evolutionally conserved, and distinguishes ZIKV from other known viruses with putative MBSs. Integrated structural analysis showed that MSI1 binds to the AUAG motif and AGAA tetraloop of ZIKV in a bipartite fashion. Thus, our results not only identified an unusual viral RNA structure responsible for MSI recognition, but also revealed a role for the highly structured xrRNA in controlling viral neurotropism.

Date: 2023
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DOI: 10.1038/s41467-023-36838-w

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