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Porcine Rotavirus VP6 Protein Wrests IPEC-J2 METTL3-Mediated M6A Modification to Fight Antiviral Immune Response

ABSTRACT: N6-methyladenosine (m6A), the most abundant mRNA modification, can regulate various mRNA metabolism to affect numerous physiological and pathophysiological processes, including immune function. However, the regulation of m6A methylation and its role in immune defense against virus infections remain unexplored. Here, we found that Porcine rotavirus (PoRV) infection decreased global m6A levels in host cells by downregulating m6A writer METTL3. Remarkably, knockdown of Mettl3 or m6A reader Ythdf2 enhances antiviral resistance in IPEC-J2 cells. Through RNA-seq and m6A -seq, we identified interferon regulatory factor 2 (IRF2) and interferon induced protein 44-like (IFI44L) as key m6A targets during PoRV infection. Silencing Mettl3 or Ythdf2 elevated mRNA stability of Irf2 and Ifi44l to restricting viral replication. Conversely, depletion of Irf2 and Ifi44l rendered host cells more susceptible to PoRV infection. Our findings uncover a novel m6A-mediated antiviral mechanism targeting the interferon response factors IRF2 and IFI44L, shedding new light on the epitranscriptomic regulation of host-pathogen interactions.

ORGANISM(S): Sus scrofa Porcine rotavirus

PROVIDER: GSE264016 | GEO | 2024/04/19

REPOSITORIES: GEO

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Project description:Background: Post-transcriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. Modifications to m6A are dynamic and reversible in cancer cells and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of m6A methylation in the Hippo pathway, a key pathway involved in cell proliferation and metabolism. Methods: First, a combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal the map of m6A modifications in breast cancer tissues and cells. Secondly, we identified the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells by performing RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis. The expression and biological functions of METTL3 and YTHDF2 were confirmed in breast cancer cell lines in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway could be affected by m6A regulation of LATS1 in breast cancer cells. Results: We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. Conclusions: In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.

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Porcine Rotavirus VP6 Protein Wrests IPEC-J2 METTL3-Mediated M6A Modification to Fight Antiviral Immune Response

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