1. PCIF1-mediated deposition of 5′-cap N6, 2′-O-dimethyladenosine in ACE2 and TMPRSS2 mRNA regulates susceptibility to SARS-CoV-2 infection.
- Author
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Lingling Wang, Shaobo Wang, Lujing Wu, Wanyu Li, Bray, William, Clark, Alex E., Gonzalez, Gwendolyn Michelle, Yinsheng Wang, Carlin, Aaron F., and Rana, Tariq M.
- Subjects
COVID-19 ,MESSENGER RNA ,ANGIOTENSIN converting enzyme ,SARS-CoV-2 - 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 (m
6 Am ), one of the most abundant modifications of eukaryotic messenger ribonucleic acid (mRNAs), in SARS-CoV-2 infection of human cells. Using genome-wide m6 Am -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 m6 Am -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 m6 Am in regulating SARS-CoV-2 susceptibility and identify a potential therapeutic target for prevention of infection. [ABSTRACT FROM AUTHOR]- Published
- 2023
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