Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections

Figures

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  Figure 1. Deamination of A in dsRNA by ADARs. (a) C6 deamination of A yields I. (b) Adenosine deamination in dsRNA is catalyzed by ADARs. In mammals, there are four ADARs, one interferon-inducible (ADAR1-p150) and three constitutively expressed (ADAR1-p110, ADAR2, and ADAR3). ADAR1-p150, ADAR1-p110, and ADAR2 possess enzymic activity, whereas ADAR3 lacks deaminase activity but can inhibit active ADARs. Abbreviations: A, adenosine; ADARs, adenosine deaminases acting on RNA; dsRNA, double-stranded RNA; G, guanosine; I, inosine. Figure adapted from Reference 15.

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  Figure 2. Domain organization of ADAR proteins. The deaminase catalytic domain (blue) is present in the C-terminal region of the active ADAR1 and ADAR2 enzymes and the inactive ADAR3 (blue columns) protein. Repeated dsRNA-binding domains (red) are designated RI, RII, and RIII. The N-terminal region of ADAR1-p150 possesses repeated copies of the Z-DNA-binding domains (pink), designated Zα and Zβ. Inducible ADAR1-p150 initiates at M1 and lacks amino acid residues 807–832 due to alternative transcript splicing; constitutive ADAR1-p110 initiates at M296 and includes amino acid residues 807–832. Human ADAR1 is sumoylated at K418; mutation of K554, K665, and K776 impairs dsRNA binding activity of the respective R domain; and mutation of Y177 of Zα impairs DNA binding activity. H910 and E912 are essential residues of the CHAE deaminase catalytic core. Abbreviations: ADARs, adenosine deaminases acting on RNA; dsRNA, double-stranded RNA; NES, nuclear export signal; NLS, nuclear localization signal. Figure adapted from Reference 7.

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  Figure 3. Organization of the human ADAR1 gene. (a) Exon-intron organization of the ~40-kbp human ADAR1 gene found on chromosome 1q21. Exons 1–15 are indicated by black boxes and include alternative exons 1A, 1B, and 1C and alternative exons 6a and 6b and 7a and 7b. Introns and 5’- and 3’-flanking regions are indicated by solid lines. (b) Alternative promoters are indicated by circles and include PiA (yellow), which is IFN inducible, and PcB, PcC, and Pc2 (green), which are constitutively active. The PiA promoter drives expression of alternative exon 1A-, exon 7b-containing transcripts that encode the 1,200-aa ADAR1-p150 protein that initiates from AUG1 present in exon 1A. Alternative exons 1B and 1C do not contain an AUG; constitutively active promoters drive expression of transcripts that initiate translation of the 931-aa ADAR1-p110 protein from the in-frame AUG296 codon present in exon 2. (c) The human ADAR1 and mouse Adar1 genes possess highly conserved PiA promoter elements (yellow) that drive the IFN-inducible expression of exon 1A-containing transcripts: a 12-bp ISRE found in type I IFN-inducible genes and an adjacent 13-bp KCS-like element, which is also found in the protein…

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  Figure 4. Effect of ADARs on virus replication and host responses to viral infection. ADARs are antiviral, proviral, or have no effect on virus infection, depending on the virus-host combination. Representative animal viruses are grouped by the biochemical nature of their genomes. The protein (ADAR1, yellow; ADAR2, blue) implicated in mediating the response, the viral or host RNA targeted by the ADAR protein, and the mechanism by which viral replication is affected are indicated. Abbreviations: ADARs, adenosine deaminases acting on RNA; AdV, adenovirus; BoDV, Borna disease virus; CHIKV, chikungunya virus; circ, circular; CoV, coronavirus; DENV, Dengue virus; DI, defective-interfering; ds, double-stranded; EBOV, Ebola virus; EBV, Epstein-Barr virus; EMCV, encephalomyocarditis virus; GP-C, glycoprotein precursor; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus; HIV, human immunodeficiency virus; HPV, human papillomavirus; HTLV, human T cell leukemia virus; IAV, influenza A virus; IRES, internal ribosome entry site; KSHV, Kaposi sarcoma–associated herpesvirus; LCMV, lymphocytic choriomeningitis virus; MeV, measles virus; MPyV, murine polyomavirus; mRNA, messenger…

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  Figure 5. Model for ADAR1 as a suppressor of innate immune responses activated by dsRNA. Cytoplasmic RLRs MDA5 and RIG-I and endosome-associated TLR3 sense intracellular dsRNA to signal via MAVS and TRIF adapters the activation of IRF and NF-κB transcription factors that transcriptionally activate IFN expression. Extracellular viral dsRNAs may be transferred into uninfected bystander cells by the surface receptors Raftlin and MSR1 and internalized and transported to the cytoplasm by SIDT1/2 to trigger innate immune dsRNA sensors. Among the ISGs induced by IFN and JAK-STAT signaling are PKR and OAS, which, when activated by cytoplasmic dsRNA, lead to translation inhibition and RNA degradation. Under conditions of ADAR1-p150 deficiency, cytoplasmic viral (nonself) and cellular (self) RNAs with ds structure accumulate to a concentration surpassing the threshold required for activation of innate immune sensors including MDA5, PKR, and OAS, thereby leading to IFN production and action. In IFN-treated cells, cytoplasmic p150 is elevated, which leads to A-to-I editing and inactivation of cellular (self) dsRNAs that then fall below the threshold concentration necessary for innate immune sensor…