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

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. [Display omitted] • RIC-seq maps SARS-CoV-2-to-host RNA-RNA interactions in infected cells • SARS-CoV-2 stabilizes host mRNAs via base pairings at 3′ UTRs • SARS-CoV-2 stabilizes host mRNAs by recruiting RNA-binding protein YBX3 • Stabilized NFKBIZ contributes to SARS-CoV-2-elicited immunopathogenesis Zhao et al. use RIC-seq technology for global profiling of SARS-CoV-2-to-host RNA-RNA interactions in infected cells. The authors find that SARS-CoV-2 RNA stabilizes host mRNAs through their 3′ UTRs via base pairings by recruiting RNA-binding protein YBX3. The stabilized host mRNA NFKBIZ may contribute to SARS-CoV-2-elicited immunopathogenesis. [ABSTRACT FROM AUTHOR]