Abstract
Signaling through retinoic acid inducible gene I (RIG-I) like receptors (RLRs) is tightly regulated, with activation occurring upon sensing of viral nucleic acids, and suppression mediated by negative regulators. Under homeostatic conditions aberrant activation of melanoma differentiation-associated protein-5 (MDA5) is prevented through editing of endogenous dsRNA by RNA editing enzyme Adenosine Deaminase Acting on RNA (ADAR1). In addition, ADAR1 is postulated to play pro-viral and antiviral roles during viral infections that are dependent or independent of RNA editing activity. Here, we investigated the importance of ADAR1 isoforms in modulating influenza A virus (IAV) replication and revealed the opposing roles for ADAR1 isoforms, with the nuclear p110 isoform restricting versus the cytoplasmic p150 isoform promoting IAV replication. Importantly, we demonstrate that p150 is critical for preventing sustained RIG-I signaling, as p150 deficient cells showed increased IFN-β expression and apoptosis during IAV infection, independent of RNA editing activity. Taken together, the p150 isoform of ADAR1 is important for preventing sustained RIG-I induced IFN-β expression and apoptosis during viral infection.
Highlights
Cell intrinsic responses against RNA viruses are primarily mediated through cytoplasmic retinoic acid inducible gene I (RIG-I) like receptors (RLRs)
We investigated the significance of host protein ADAR1 and different isoforms of ADAR1 in influenza virus replication
Influenza virus replication was increased in cells lacking the p110 isoform of ADAR1, indicating that p110 hinders influenza virus replication
Summary
Cell intrinsic responses against RNA viruses are primarily mediated through cytoplasmic retinoic acid inducible gene I (RIG-I) like receptors (RLRs). RIG-I or MDA5 translocate to the mitochondrial membrane and interact with mitochondrial antiviral signaling protein (MAVS) [8]. Tank binding kinase (TBK1) and inhibitor of nuclear factor kappa B kinase (IKKb) are recruited to the RLR-MAVS complex to phosphorylate and activate the transcription factors interferon regulator factor 3 (IRF3) and nuclear factor kappa B (NF-kB), which subsequently translocate to the nucleus to initiate transcription of interferon-β (IFN-β) and other proinflammatory cytokines, respectively [9,10,11,12]. Secreted IFN signals in an autocrine or paracrine manner by binding to IFN receptors and activating the Janus kinase (JAK) and signal transducer and activators of transcription (STAT) pathway, which results in transcriptional upregulation of >300 interferon stimulated genes (ISGs) [13]. Through a variety of mechanisms, these induced ISGs restrict viral replication in infected cells as well as create an antiviral state in the surrounding cells
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