Zalpha-domains: At the intersection between RNA editing and innate immunity

Alekos Athanasiadis

doi:10.1016/j.semcdb.2011.11.001

Abstract

The involvement of A to I RNA editing in antiviral responses was first indicated by the observation of genomic hyper-mutation for several RNA viruses in the course of persistent infections. However, in only a few cases an antiviral role was ever demonstrated and surprisingly, it turns out that ADARs – the RNA editing enzymes – may have a prominent pro-viral role through the modulation/down-regulation of the interferon response. A key role in this regulatory function of RNA editing is played by ADAR1, an interferon inducible RNA editing enzyme. A distinguishing feature of ADAR1, when compared with other ADARs, is the presence of a Z-DNA binding domain, Zalpha. Since the initial discovery of the specific and high affinity binding of Zalpha to CpG repeats in a left-handed helical conformation, other proteins, all related to the interferon response pathway, were shown to have similar domains throughout the vertebrate lineage. What is the biological function of this domain family remains unclear but a significant body of work provides pieces of a puzzle that points to an important role of Zalpha domains in the recognition of foreign nucleic acids in the cytoplasm by the innate immune system. Here we will provide an overview of our knowledge on ADAR1 function in interferon response with emphasis on Zalpha domains.

Highlights

These findings indicate that any extensive and stable pre-mRNA stem-loop structure is accessible to ADARs and a potential target for RNA editing and have led to a wide rethinking regarding the primary role of this post-transcriptional modification
In vertebrate species we find two genes encoding for active dsRNA dependent adenosine deaminases: ADAR1 and ADAR2
An attractive model based on the available data ascribes a dual function of ADAR1: in the nucleus, it keeps under control the amount of cellular dsRNA that can reach dsRNA sensors in the cytoplasm while upon prolonged activation of the interferon pathway the P150 isoform migrates to the cytoplasm where it downregulates antiviral responses by limiting the available dsRNA

Summary

Modification of viral nucleic acids

Viral nucleic acids have been among the first known substrates of ADARs: the discovery of hyper-mutated RNA genomes of measles virus [18] and other members of the paramyxoviridae family was followed by similar observations for Vesicular Stomatitis Virus and mRNAs of the mouse polyoma DNA-virus reviewed in [19,20,21]. More recently similar hypermutation was observed in the invertebrate sigma RNA-virus [22] involving the ADAR enzyme of drosophilids These findings were taken to suggest an antiviral role of ADAR mediated RNA editing, mechanistically based on scrambling the information content of viral nucleic acids, not unlike the role of the APOBEC3 family of cytidine deaminases in retroviral restriction. Specific RNA editing has been found in transcripts of the Kaposi sarcoma associated virus (KSHV) [28,29], where again RNA editing appears to be adapted by the virus as the levels of editing correlate with the replicative state of the virus [29] For both the hyper-editing and the more specific editing events observed in viral nucleic acids there is no clear evidence that these base modifications overall represent an antiviral action of ADARs. On the contrary, for viruses like Hepatitis D, RNA editing represents a valuable cellular contribution

ADAR1 as a regulator of antiviral responses

The ADAR1 Zalpha domain

The ADAR1 Zalpha domain structure and its nucleic acids complexes

The non-conforming Zbeta

Findings

Nucleic acids bound by Zalpha in vivo