RNA m⁶ A modification enzymes shape innate responses to DNA by regulating interferon β

Area of Science:

• Immunology
• Epigenetics
• Virology

Background:

• N6-adenosine methylation (m6A) is a crucial epitranscriptomic modification regulating gene expression in eukaryotes.
• The role of dynamic m6A landscapes in virus infection and host immune responses is not well understood.

Purpose of the Study:

• To investigate how cellular m6A modification enzymes, METTL14 and ALKBH5, regulate type I interferon production in response to dsDNA and human cytomegalovirus (HCMV).
• To elucidate the impact of m6A machinery on host antiviral immunity and cellular responses to non-microbial dsDNA.

Main Methods:

• Depletion of METTL14 and ALKBH5 in cells.
• Analysis of IFNB1 mRNA production, stability, and nascent transcription.
• Genome-wide transcriptome profiling.
• m6A modification analysis of IFNB1 mRNA.

Main Results:

• METTL14 depletion reduced viral replication and enhanced dsDNA/HCMV-induced IFNB1 mRNA accumulation, increasing nascent production and stability.
• ALKBH5 depletion had opposing effects, reducing nascent IFNB1 mRNA production without affecting mRNA decay.
• Genome-wide analysis revealed METTL14 depletion impacts metabolic and stress pathways, while ALKBH5 depletion affects antiviral immune response genes.
• IFNB1 mRNA was found to be m6A-modified in both coding and untranslated regions.

Conclusions:

• The host m6A modification machinery, specifically METTL14 and ALKBH5, plays a critical role in controlling type I interferon production triggered by HCMV or dsDNA.
• Epitranscriptomic regulation by m6A enzymes influences host antiviral immunity and cellular responses to non-microbial dsDNA, with implications for autoimmune diseases.