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Review
. 2019 Feb 1;294(5):1710-1720.
doi: 10.1074/jbc.TM118.004166.

Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA-triggered innate immune responses

Charles E Samuel  1
Affiliations
Review

Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA-triggered innate immune responses

Charles E Samuel. J Biol Chem. .

Abstract

Herbert "Herb" Tabor, who celebrated his 100th birthday this past year, served the Journal of Biological Chemistry as a member of the Editorial Board beginning in 1961, as an Associate Editor, and as Editor-in-Chief for 40 years, from 1971 until 2010. Among the many discoveries in biological chemistry during this period was the identification of RNA modification by C6 deamination of adenosine (A) to produce inosine (I) in double-stranded (ds) RNA. This posttranscriptional RNA modification by adenosine deamination, known as A-to-I RNA editing, diversifies the transcriptome and modulates the innate immune interferon response. A-to-I editing is catalyzed by a family of enzymes, adenosine deaminases acting on dsRNA (ADARs). The roles of A-to-I editing are varied and include effects on mRNA translation, pre-mRNA splicing, and micro-RNA silencing. Suppression of dsRNA-triggered induction and action of interferon, the cornerstone of innate immunity, has emerged as a key function of ADAR1 editing of self (cellular) and nonself (viral) dsRNAs. A-to-I modification of RNA is essential for the normal regulation of cellular processes. Dysregulation of A-to-I editing by ADAR1 can have profound consequences, ranging from effects on cell growth and development to autoimmune disorders.

Keywords: 2'-5'-oligoadenylate synthetase; ADAR; RIG-I–like receptor (RLR); RNA deamination; RNA editing; adenosine deaminase acting on RNA; double-stranded RNA (dsRNA); innate immunity; interferon; protein kinase PKR.

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Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

Figures

Figure 1.
Figure 1.
RNA editing by ADARs. Upper panel, C6 deamination of adenosine (A) in duplex RNA to produce inosine (I) catalyzed by ADARs. ADAR1, both the IFN-inducible p150 and the constitutively expressed p110, and ADAR2 possess deaminase activity. ADAR3 lacks deaminase activity and is implicated as a negative regulator of editing by ADAR1 and ADAR2. Lower panel, domain organization of ADAR proteins. The nucleic acid–binding domains include repeated dsRNA-binding domains (red, RI, RII, and RIII), either two (ADAR2 and ADAR3) or three (ADAR1 p110 and p150) copies. The N-terminal region of ADAR1 p150 possesses two copies of a Z-DNA–binding domain (pink, Zα and Zβ), and ADAR3 has an arginine-rich ssRNA-binding domain (green, ARG). The deaminase catalytic domain (yellow) is C terminus; ADAR3 (cross-hatched yellow) is not yet demonstrated to possess enzymatic activity. (Adapted from Ref. .)
Figure 2.
Figure 2.
Biochemical mechanisms by which A-to-I editing of RNA transcripts possessing double-stranded structure may affect gene expression and product function. Because I base-pairs as G instead of A, A-to-I RNA editing has the capacity to alter processes, including mRNA translation by altering codons and hence coding potential, pre-mRNA splicing by changing splice site recognition sequences, and RNA silencing by altering microRNA production or targeting. A-to-I editing may also lead to RNA mutations of viral genomes and transcripts by changing template and hence product sequences during RNA-dependent RNA replication. Finally, A-to-I editing may lead to I-U mismatches in place of A:U bp, thereby destabilizing dsRNA structures and hence affecting the activity of dsRNA sensing proteins of the interferon response, including the MDA5 RIG-I–like receptor, protein kinase PKR, and 2′-5′-oligoadenylate synthetase OAS–RNase L. (Adapted from Ref. .)
Figure 3.
Figure 3.
Model summarizing the role of ADAR1 as a suppressor of dsRNA-triggered innate immune responses. Cytoplasmic RLR and endosomal membrane-associated TLR3 sense dsRNA to mediate the production of type I IFN through activation of interferon-regulatory (IRF) and NF-κB transcription factors. The RLR family of proteins includes the MDA5 sensor that detects cytoplasmic dsRNAs, both viral (nonself) and cellular (self), and signals via the mitochondrial adaptor MAVS (IPS-1 and VISA) to produce IFN. Among the IFN-induced proteins are the PKR protein kinase and OAS synthetases, also cytoplasmic dsRNA-binding proteins. PKR, when activated by dsRNA-dependent autophosphorylation, phosphorylates translation initiation factor eIF2α thereby leading to an inhibition of translation. OAS, when activated by dsRNA, produces 2′-5′-oligoadenylates, which then activate the 2–5A–dependent RNase L thereby leading to RNA degradation. The p150 isoform of ADAR1 is IFN-inducible and both cytoplasmic and nuclear, whereas ADAR1 p110 and ADAR2 are both nuclear proteins and constitutively expressed. Under conditions of ADAR1 p150 deficiency, cellular RNAs (self) with double-stranded structure accumulate to sufficiently high concentration, above the threshold, and trigger activation of cytoplasmic dsRNA sensors, including MDA5, PKR, and OAS. In the presence of ADAR1 p150, A-to-I editing leads to inactivation of cellular (self) dsRNAs and impairment of dsRNA-triggered innate immune responses, as the dsRNA concentration is below the threshold. Infection leads to increased levels of viral dsRNA (nonself) present in infected cells compared with the cellular dsRNA (self) present in uninfected cells, thereby triggering activation of dsRNA sensors MDA5, PKR, and OAS. (Adapted from Ref. .)
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