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Zhao, Guangze; Zhang, Huifang M.; Chen, Yankuan T.; Shi, Kerry; Aghakeshmiri, Sana; Yip, Fione; Luo, Honglin; McManus, Bruce; Yang, Decheng

Multidisciplinary Digital Publishing Institute

N6-methyladenosine (m⁶A) is the most prevalent internal RNA modification. Here, we demonstrate that coxsackievirus B3 (CVB3), a common causative agent of viral myocarditis, induces m⁶A 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 m⁶A machinery components—METTL3, ALKBH5 and YTHDFs—resulting in increased m⁶A 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 m6A modifications enhance viral replication by regulating YTHDF-mediated SG dynamics. This study provides a potential therapeutic strategy for CVB3-induced myocarditis.

Article

eng

Vancouver : University of British Columbia Library

10.14288/1.0447365

Medicine, Faculty of; Other UBC; Pathology and Laboratory Medicine, Department of

10.3390/microorganisms12112152

Faculty; Researcher

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