Open AccessN6-methyladenosine promotes induction of ADAR1-mediated A-to-I RNA editing to suppress aberrant antiviral innate immune responses
Author(s) -
Hideki Terajima,
Mijia Lu,
Linda Zhang,
Qi Cui,
Yanhong Shi,
Jiànróng Lǐ,
Chuan He
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001292
Subject(s) - rna editing , biology , rna , rna silencing , innate immune system , interferon , rna binding protein , gene knockdown , microbiology and biotechnology , transcription (linguistics) , inosine , rna interference , adenosine , biochemistry , gene , genetics , immune system , linguistics , philosophy
Among over 150 distinct RNA modifications, N 6 -methyladenosine (m 6 A) 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 m 6 A 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 N 6 -methyladenosine RNA binding protein 1 (YTHDF1) mediates up-regulation of ADAR1; YTHDF1 is a reader protein that can preferentially bind m 6 A-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 m 6 A and YTHDF1 affect innate immune responses through modulating the ADAR1-mediated A-to-I RNA editing.