Faculty, Staff and Student Publications

Publication Date

12-1-2025

Journal

RNA Biology

DOI

10.1080/15476286.2025.2527494

PMID

40590376

PMCID

PMC12239786

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

SARS-CoV-2 is the betacoronavirus causing the COVID-19 pandemic. Although the SARS-CoV-2 genome and transcriptome were reported previously, the function of individual viral proteins is largely unknown. Utilizing biochemical and molecular biology methods, we identified that four SARS-CoV-2 RNA-binding proteins (RBPs) regulate the host RNA metabolism by direct interaction with mature miRNA let-7b revealed by Nuclear Magnetic Resonance spectroscopy (NMR). SARS-CoV-2 RBP Nsp9 primarily binds mature miRNA let-7b, a direct ligand of the Toll-like Receptor 7 (TLR7), one of the potential SARS-CoV-2 therapeutics. Nsp9 suppresses host gene expression possibly by promoting let-7b-mediated silencing of a cellular RNA polymerase, POLR2D. In addition, Nsp9 inhibits extracellular release of let-7b and subsequent antiviral activity via TLR7. These results demonstrate that SARS-CoV-2 hijacks the host RNA metabolism to suppress antiviral responses and to shut down cellular transcription. Our findings of how a natural ligand of TLR7, miRNA let-7b, is suppressed by SARS-CoV-2 RBPs will advance our understanding of COVID-19 and SARS-CoV-2 therapeutics.

Keywords

MicroRNAs, Humans, SARS-CoV-2, RNA-Binding Proteins, COVID-19, Toll-Like Receptor 7, Viral Nonstructural Proteins, HEK293 Cells, Protein Binding, Host-Pathogen Interactions, SARS-CoV-2, Nsp9, miRNA, let-7b, POLR2D

Published Open-Access

yes

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