Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections

Abstract

C6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA) encoded by three genes in mammals. Alternative promoters and splicing produce two ADAR1 proteins, an interferon-inducible cytoplasmic p150 and a constitutively expressed p110 that like ADAR2 is a nuclear enzyme. ADAR3 lacks deaminase activity. A-to-I editing occurs with both viral and cellular RNAs. Deamination activity is dependent on dsRNA substrate structure and regulatory RNA-binding proteins and ranges from highly site selective with hepatitis D RNA and glutamate receptor precursor messenger RNA (pre-mRNA) to hyperediting of measles virus and polyomavirus transcripts and cellular inverted Alu elements. Because I base-pairs as guanosine instead of A, editing can alter mRNA decoding, pre-mRNA splicing, and microRNA silencing. Editing also alters dsRNA structure, thereby suppressing innate immune responses including interferon production and action. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response

“…Furthermore, we performed Panther—Gene Ontology (GO) Enrichment Analysis for molecular functions on “in transition” microglia/microglia-like cell cluster, using all significantly up-regulated genes (P < 0.05). The analysis revealed the following upregulated GO terms: “Protein homodimerization activity,” “Chemokine receptor binding,” “Cytokine binding,” “Cytokine activity,” “Carbohydrate derivative binding,” “Nucleotide binding,” “GTPase activity,” and “Enzyme binding.” Interestingly, “double-stranded RNA binding” function, regrouping 6 genes ( Ifih1 , Adar , Oas2 , Oas3 , Oasl1, and Oasl2 ) involved in the antiviral response, including IFN downstream signaling, were identified for this microglial sub-cluster [ 56 – 58 ]. Indeed, the assessment of differential expression levels of a homemade gene set demonstrated upregulated expression levels of genes encoding antiviral proteins and IFN-related genes, such as Isg15 , Ifi47 , Irf7 , Ifit1 , for the “in transition” microglia/microglia-like cells (Fig.…”

Arbovirus-vector protein interactomics identifies Loquacious as a co-factor for dengue virus replication in Aedes mosquitoes

“…Among the potential antiviral factors from our screen are RNA binding proteins DIP1, an ortholog of human ADAR proteins to which pro- and antiviral activities have been attributed [50, 51], and RPL12 (RPA12), which could modulate viral replication through its dsRNA cleavage and transcriptional termination activities [52]. In addition, we found the ER retention protein RER1 involved in protein degradation via the proteasome [53] and the chaperone protein HSP60A [54] to be antiviral factors, possibly related to a role of the stress response in antiviral immunity [55].…”

The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity

“…The difference is that inosine generally acts similarly to guanosine (G), whereas ψ remains the original capacity of uridine to some extent. Although U to ψ conversion does not change the Watson-Crick base-pairing with adenosine, in certain cases, ψ enables base pairing with any other nucleotides (Samuel, 2011;Pfaller et al, 2021). Both ψ and A-to-I editing may significantly convert RNA biology, including changing the coding preference of viral RNA dependent RNA polymerases, mediating alternative splice and even affecting RNA structures (Netzband and Pager, 2020;Pfaller et al, 2021).…”

“…Other studies also indicate an important role of ADARs, the enzymes mediating A-to-I editing, in modulating innate immune response during virus infection (Pfaller et al, 2021). ADAR1 has a proviral effect on Measles virus (MeV) and VSV infection that depends on PKR activation (Nie et al, 2007;Pfaller et al, 2015), while the suppression of innate immune response by ADAR2 is supposed to rely on STAT1 in the case of Chikungunya virus (CHIKV) and Venezuelan equine encephalitis virus (VEEV; Schoggins et al, 2011;Clavarino et al, 2012).…”

“…ADAR1 has a proviral effect on Measles virus (MeV) and VSV infection that depends on PKR activation (Nie et al, 2007;Pfaller et al, 2015), while the suppression of innate immune response by ADAR2 is supposed to rely on STAT1 in the case of Chikungunya virus (CHIKV) and Venezuelan equine encephalitis virus (VEEV; Schoggins et al, 2011;Clavarino et al, 2012). In the case of other viruses, such as BoDV, IAV, and Yellow fever virus (YFV), the mechanisms of ADARregulated IFN response remain indistinct (Pfaller et al, 2021). Interestingly, during HIV-1 infection, ADAR1 and ADAR2 may have opposite effects on virus replication, through the forming of DNA:RNA heteroduplex or antiviral innate immune response, respectively (Clerzius et al, 2009;Doria et al, 2009;Pujantell et al, 2017).…”