Post by Nadica (She/Her) on Nov 13, 2024 3:50:56 GMT
SARS-CoV-2 RNA stabilizes host mRNAs to elicit immunopathogenesis - Published Feb 1, 2024
Highlights
• 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
Summary
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.
Graphical abstract
Highlights
• 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
Summary
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.
Graphical abstract