Abstract
Among over 150 distinct RNA modifications, N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) RNA editing represent 2 of the most studied modifications on mammalian mRNAs. Although both modifications occur on adenosine residues, knowledge on potential functional crosstalk between these 2 modifications is still limited. Here, we show that the m6A modification promotes expression levels of the ADAR1, which encodes an A-to-I RNA editing enzyme, in response to interferon (IFN) stimulation. We reveal that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) mediates up-regulation of ADAR1; YTHDF1 is a reader protein that can preferentially bind m6A-modified transcripts and promote translation. Knockdown of YTHDF1 reduces the overall levels of IFN-induced A-to-I RNA editing, which consequently activates dsRNA-sensing pathway and increases expression of various IFN-stimulated genes. Physiologically, YTHDF1 deficiency inhibits virus replication in cells through regulating IFN responses. The A-to-I RNA editing activity of ADAR1 plays important roles in the YTHDF1-dependent IFN responses. Therefore, we uncover that m6A and YTHDF1 affect innate immune responses through modulating the ADAR1-mediated A-to-I RNA editing.
Highlights
Posttranscriptional regulation plays a pivotal role in ensuring proper gene expression in almost all organisms
Our results indicate that the YTHDF1-mediated induction of ADAR1p150 and its editing activity are critical for preventing undesirable activation of MDA5, which could cause phosphorylation of TANK-binding kinase 1 (TBK1) and excessive downstream IFN production during IFN response
A role of N6-methyladenosine in innate immunity possible that YTHDF1 can directly affect viral protein expression because a very recent study showed that VSV viral transcripts have m6A sites [50], and our study revealed that YTHDF proteins affect the expression levels of viral G protein through binding to m6A sites in their mRNA [51]
Summary
Posttranscriptional regulation plays a pivotal role in ensuring proper gene expression in almost all organisms. Recent studies have shown that ADAR1-mediated A-to-I RNA editing disrupts secondary structures of dsRNA to prevent self-activation of cytosolic viral dsRNA sensors that induce IFN production and downstream ISGs, contributing to antiviral immunity [23] These observations prompted us to explore potential roles of YTHDF1 in the IFN signaling. YTHDF1 knockdown significantly increased the expression levels of IFN genes, ISGs, and NF-κB–regulated genes at early time points after VSV infection (Fig 5C) These results indicated that YTHDF1 depletion enhances cellular antiviral activities through increasing IFN responses during viral infection. The enhanced mRNA expression of IFN genes, ISGs, and NF-κB–regulated genes were partially suppressed by ADAR1p150 overexpression (Fig 5F), which is consistent with the increased viral replication in ADAR1p150-overexpressing cell lines These effects were not observed or diminished by overexpression of mutant ADAR1p150E912A (Figs 5D–5F and S5D and S5E). Loss of YTHDF1 exhibited the antiviral activities following with the enhanced IFN responses
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