Molecular Cell, 20 December, 2023, DOI：https://doi.org/10.1016/j.molcel.2023.11.032

SARS-CoV-2 RNA stabilizes host mRNAs to elicit immunopathogenesis

Hailian Zhao, Zhaokui Cai, Jian Rao, Di Wu, Lei Ji, Rong Ye, Di Wang, Juan Chen, Changchang Cao, Naijing Hu, Ting Shu, Ping Zhu, Jianwei Wang, Xi Zhou, Yuanchao Xue

Abstract

SARS-CoV-2 RNA interacts with host factors to suppress interferon responses and simultaneously induces cytokine release to drive the development of severe coronavirus disease 2019 (COVID-19). However, how SARS-CoV-2 hijacks host RNAs to elicit such imbalanced immune responses remains elusive. Here, we analyzed SARS-CoV-2 RNA in situ structures and interactions in infected cells and patient lung samples using RIC-seq. We discovered that SARS-CoV-2 RNA forms 2,095 potential duplexes with the 3′ UTRs of 205 host mRNAs to increase their stability by recruiting RNA-binding protein YBX3 in A549 cells. Disrupting the SARS-CoV-2-to-host RNA duplex or knocking down YBX3 decreased host mRNA stability and reduced viral replication. Among SARS-CoV-2-stabilized host targets, NFKBIZ was crucial for promoting cytokine production and reducing interferon responses, probably contributing to cytokine storm induction. Our study uncovers the crucial roles of RNA-RNA interactions in the immunopathogenesis of RNA viruses such as SARS-CoV-2 and provides valuable host targets for drug development.

Article link：https://www.sciencedirect.com/science/article/pii/S1097276523009784?via%3Dihub