Coxsackievirus B3-Induced m<sup>6</sup>A Modification of RNA Enhances Viral Replication via Suppression of YTHDF-Mediated Stress Granule Formation

Coxsackievirus B3-Induced m<sup>6</sup>A Modification of RNA Enhances Viral Replication via Suppression of YTHDF-Mediated Stress Granule Formation

N6-methyladenosine (m<sup>6</sup>A) is the most prevalent internal RNA modification. Here, we demonstrate that coxsackievirus B3 (CVB3), a common causative agent of viral myocarditis, induces m<sup>6</sup>A modification primarily at the stop codon and 3′ untranslated regions...

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Bibliographic Details
Main Authors: Guangze Zhao, Huifang M. Zhang, Yankuan T. Chen, Kerry Shi, Sana Aghakeshmiri, Fione Yip, Honglin Luo, Bruce McManus, Decheng Yang
Format: Article
Language:English
Published: MDPI AG 2024-10-01
Series:Microorganisms
Subjects:
coxsackievirus B3
N6-methyladenosine
HuR
3D
reader protein YTHDFs
stress granule
Online Access:https://www.mdpi.com/2076-2607/12/11/2152
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Summary:N6-methyladenosine (m<sup>6</sup>A) is the most prevalent internal RNA modification. Here, we demonstrate that coxsackievirus B3 (CVB3), a common causative agent of viral myocarditis, induces m<sup>6</sup>A modification primarily at the stop codon and 3′ untranslated regions of its genome. As a positive-sense single-stranded RNA virus, CVB3 replicates exclusively in the cytoplasm through a cap-independent translation initiation mechanism. Our study shows that CVB3 modulates the expression and nucleo-cytoplasmic transport of the m<sup>6</sup>A machinery components—METTL3, ALKBH5 and YTHDFs—resulting in increased m<sup>6</sup>A modifications that enhance viral replication. Mechanistically, this enhancement is mediated through YTHDF-driven stress granule (SG) formation. We observed that YTHDF proteins co-localize with human antigen R (HuR), a protein facilitating cap-independent translation, in SGs during early infection. Later in infection, YTHDFs are cleaved, suppressing SG formation. Notably, for the first time, we identified that during early infection CVB3’s RNA-dependent RNA polymerase (3D) and double-stranded RNA (dsRNA) are stored in SGs, co-localizing with HuR. This early-stage sequestration likely protects viral components for use in late-phase replication, when SGs are disrupted due to YTHDF cleavage. In summary, our findings reveal that CVB3-induced m<sup>6</sup>A modifications enhance viral replication by regulating YTHDF-mediated SG dynamics. This study provides a potential therapeutic strategy for CVB3-induced myocarditis.
ISSN:2076-2607

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