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1.
Proc Natl Acad Sci U S A ; 120(5): e2210361120, 2023 Jan 31.
Article in English | MEDLINE | ID: covidwho-2236812

ABSTRACT

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a major health problem worldwide. Due to the fast emergence of SARS-CoV-2 variants, understanding the molecular mechanisms of viral pathogenesis and developing novel inhibitors are essential and urgent. Here, we investigated the potential roles of N6,2'-O-dimethyladenosine (m6Am), one of the most abundant modifications of eukaryotic messenger ribonucleic acid (mRNAs), in SARS-CoV-2 infection of human cells. Using genome-wide m6Am-exo-seq, RNA sequencing analysis, and Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing, we demonstrate that phosphorylated C-terminal domain (CTD)-interacting factor 1 (PCIF1), a cap-specific adenine N6-methyltransferase, plays a major role in facilitating infection of primary human lung epithelial cells and cell lines by SARS-CoV-2, variants of concern, and other coronaviruses. We show that PCIF1 promotes infection by sustaining expression of the coronavirus receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) via m6Am-dependent mRNA stabilization. In PCIF1-depleted cells, both ACE2/TMPRSS2 expression and viral infection are rescued by re-expression of wild-type, but not catalytically inactive, PCIF1. These findings suggest a role for PCIF1 and cap m6Am in regulating SARS-CoV-2 susceptibility and identify a potential therapeutic target for prevention of infection.


Subject(s)
COVID-19 , Humans , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2 , RNA, Messenger/genetics , Nuclear Proteins/genetics , Adaptor Proteins, Signal Transducing/genetics , Serine Endopeptidases
2.
Cell Rep ; 35(6): 109091, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1213072

ABSTRACT

It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.


Subject(s)
COVID-19/genetics , Methyltransferases/metabolism , SARS-CoV-2/genetics , Adenosine/metabolism , COVID-19/metabolism , Cell Line , DEAD Box Protein 58/genetics , DEAD Box Protein 58/metabolism , Humans , Immunity, Innate/genetics , Methylation , Methyltransferases/genetics , RNA, Viral/genetics , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction
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