The Epitranscriptome and Innate Immunity

Abstract

Our knowledge of the variety and abundances of RNA base modifications is rapidly increasing. Modified bases have critical roles in tRNAs, rRNAs, translation, splicing, RNA interference, and other RNA processes, and are now increasingly detected in all types of transcripts. Can new biological principles associated with this diversity of RNA modifications, particularly in mRNAs and long non-coding RNAs, be identified? This review will explore this question by focusing primarily on adenosine to inosine (A-to-I) RNA editing by the adenine deaminase acting on RNA (ADAR) enzymes that have been intensively studied for the past 20 years and have a wide range of effects. Over 100 million adenosine to inosine editing sites have been identified in the human transcriptome, mostly in embedded Alu sequences that form potentially innate immune-stimulating dsRNA hairpins in transcripts. Recent research has demonstrated that inosine in the epitranscriptome and ADAR1 protein establish innate immune tolerance for host dsRNA formed by endogenous sequences. Innate immune sensors that detect viral nucleic acids are among the readers of epitranscriptome RNA modifications, though this does preclude a wide range of other modification effects.

Fig 1. A schematic representation of the ADAR and related ADAD proteins present in humans.

All proteins have dsRNA binding domains (grey box) and a C-terminal deaminase domain (purple box). A nuclear localization sequence (NLS) is marked in red, whereas the nuclear export signal (NES) present in ADAR1 is marked in green. Z-DNA binding domains are indicated by an orange box in ADAR1. A region enriched in arginine/lysine residues, R domain is present in ADAR3 (blue box). The number of amino acids is indicated on the right.

Fig 2. A model for the role of ADAR1 in innate immunity.

(A) DsRNA that is generated during transcription is edited by ADARs. The dsRNA contain inosine that can bind to the RLRs, MDA5 and RIG-I, in the cytoplasm and inhibit their activation. (B) During a viral infection, or if ADAR1 is inactive, unedited dsRNA is present in the cytoplasm. This dsRNA binds to MDA5 and RIG-I, activating MAVS which, in turn, leads to the phosphorylation of IRF3 and its translocation into the nucleus and induces the type 1 interferon response. (C) The ADAR1 isoform p150 is induced by interferon late in the response. This isoform is predominantly cytoplasmic and it edits all dsRNA either of viral or cellular origin. This generates inosine containing dsRNA that can inhibit the RLR receptors, thus turning off the interferon response as the transcription factor IRF9 is unable to continue to transcribe the ISGs.