N6-methyladenosine promotes induction of ADAR1-mediated A-to-I RNA editing to suppress aberrant antiviral innate immune responses

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.

RNA modification of an RNA modifier prevents self-RNA sensing

“…Abbreviations: ADAR1, adenosine deaminase acting on RNA 1; AGS, Aicardi-Goutières syndrome; A-to-I, adenosine-to-inosine; dsRNA, double-stranded RNA; IFN, interferon; MDA5, melanoma differentiation-associated protein 5; m 6 A, N6-methyladenosine; PRR, pattern recognition receptor; RIG, retinoic acid-inducible gene I; ssRNA, single-stranded RNA; YTHDF1, YTH N6-methyladenosine RNA binding protein 1.…”

“…negative impacts on viral infection due to either direct effects on viral RNA or indirect effects on cellular mRNAs that encode factors important for the immune response [4,5]. For example, m 6 A on IFNB1, which encodes the cytokine IFN-β, decreases its mRNA half-life, and m 6 A on antiviral mRNAs can influence their expression by increasing translation or decreasing stability. Thus, modifications to RNA, including m 6 A and A-to-I editing, can play important and diverse roles in viral infection and the host innate immune response.…”

“…In a new study published in PLOS Biology, Terajima and colleagues seek to understand the intersection of m 6 A and A-to-I editing, using glioblastoma cells as a model [6]. Previous studies identified a conserved m 6 A site in the ADAR1 transcript and an inverse relationship between m 6 A and A-to-I editing, suggesting that a causal link between m 6 A modification on ADAR1 and A-to-I editing might exist. This new work reveals that the m 6 A RNA-binding protein called YTH N6-methyladenosine RNA binding protein 1 (YTHDF1AU : PleasenotethatYTHDF1ha…”

“…This study by Terajima and colleagues broadens our understanding of how RNA modifications can directly control gene expression and indirectly regulate innate immune signaling, all of which could contribute to autoimmune disorders, leaving the field with much to consider for future study. For example, the depletion of YTHDF1 resulted in increased dsRNA and IFN induction, suggesting that m 6 A and its regulatory proteins could have important roles in preventing autoinflammation. Interestingly, in the cell types tested, this regulation was unique to glioblastoma cells as other cell types did not induce IFN in response to YTHDF1 depletion, suggesting that this might be a mechanism shared in human cells of glial origin.…”

“…Interestingly, the source of dsRNA produced in response to IFN treatment of glioblastoma cells is also unknown. IFN does not globally alter the frequency of Alu elements, a common source of dsRNA [7,8], although more dsRNA is produced in response to IFN in glioblastoma cells [6]. Thus, it remains to be determined if specific classes of mRNAs with secondary structure are induced by IFN and then edited by ADAR1 p150, as they are in response to bacterial lipopolysaccharide, or if there are RNA processing defects that induce more dsRNA independent of Alu repeats, as seen by others [9,10].…”