Long Non-Coding RNAs Can Govern the Antiviral Immune Response Through Interferon-Mediated Mechanisms in Respiratory Tract

Abstract

Many long non-coding RNAs (lncRNAs) are able to control interferon-dependent innate immune responses and the susceptibility to influenza infection. These lncRNAs are primarily regulated through the RIG-I/IFN-β/IFNAR1 pathway and can be considered as interferon-stimulated genes with either antiviral or proviral functions. In this review we observe the current knowledge of type I and III interferon signaling regulation and discuss the present data on specific lncRNAs, which are involved in the interferon response. The available data on mechanisms of lncRNA induction and action are summarized. Also, the brief overview of genes coding for lncRNAs involved in interferon expression regulation is presented with a focus on the evolutionary conservation of these regulatory molecules. The lncRNAs belong to various classes: antisense, bidirectional, intronic, or intergenic RNAs. Research of lncRNAs is an extremely promising scientific area. Deeper understanding of lncRNA functions may result in the development of new approaches to influenza infection treatment, as well as advanced understanding of the disease pathogenesis. Further bioinformatic analysis of lncRNAs is required to reveal putative common mechanisms of lncRNA action.

Keywords: Influenza A virus; innate immunity; interferons; long non-coding RNAs.

Figure 1

General overview of IFN induction and type I or III IFN signaling. Foreign and viral RNAs induce PRR activation. Cytosolic RNA sensor RIG-I plays significant role in the detection of invading RNA with specific features (5′-diphosphate or 5′-triphosphate group, duplex structure, no ribose 2′-O-methylation). TRIM25 stimulates K63-linked RIG-I ubiquitination and activates downstream signaling pathways. Activated multimeric form of RIG-I interacts with its protein adaptor (MAVS), which acts as a scaffold protein, activates IRF3 and NF-κB transcription factors, and induces IFN expression. Type I and III IFNs act in autocrine or paracrine manner, bind to their heterodimeric receptors, and induce JAK/STAT pathways activation. IFN action can result in ISGF3 complex assembly (IRF9/STAT1/STAT2) that induces the expression of ISRE-containing ISGs (Mx1, ISG15, IFIT1-3, OAS1-3, OASL, USP18, ISG20). Also, the expression of IRF7 is upregulated by ISGF3, IRF7 binds to the type I and type III IFN promoters, which results in feedforward loop and IFN expression amplification. Alternatively, GAF complex assembly (STAT1 homodimer) induces GAS-containing gene expression (IRF1, IRF8, SOCS3). Several ISGs possess both ISRE and GAS regulatory sequences (STAT1, STAT2, IRF9, IFITM1, SOCS1). Type I IFN-induced STAT3 homodimer inhibits STAT1-mediated antiviral response. IKK-ε also suppresses STAT1 homodimer formation, facilitating ISGF3 assembly and promoting antiviral response. Genes that attenuate JAK/STAT signaling are indicated in blue (SOCS1, SOCS3, USP18), and genes promoting JAK/STAT signaling are depicted in red (IRF1, IRF9, STAT1, STAT2). Red arrows represent activation; blue arrows–inhibition; black–secretion/gene expression; light blue ellipses–regulatory factors; red ellipses–IFN expression upregulating factors; P–phosphorylation; Ub–ubiquitination.

Figure 2

The influence of lncRNAs on RIG-I/MAVS-dependent IFN induction. Foreign and viral RNAs induce the activation of RIG-I/MAVS pathways and IFN expression. TRIM25 stimulates K63-linked ubiquitination and facilitates the innate immune response. In epithelial cells and macrophages, lncRNAs are able to modulate IFN expression at several levels at once: they regulate RIG-I production and activation (LINC02574, RNA5SP141); TRIM25-mediated RIG-I ubiquitination (HCG4, Lnczc3h7a, Lnc-Lsm3b, LncNSPL, RPS6P3); IRF3 activation (LncRNA-155, THRIL, PCBP1-AS1, USP30-AS1); IFN promoter activation (Lnc-MxA, Lnc-AROD); or histone-modifying factor action (IVRPIE). Red arrows represent the activation of IFN upregulating pathways by lncRNAs; blue arrows represent inhibitory lncRNA action; green arrows represent signaling events causing IFN expression; light blue ellipses represent proteins/factors; a combination of a lncRNA and a protein (for example, IVRPIE and SAFA) indicates their direct interaction; miRNAs are depicted in blue, mRNAs are depicted in red, and Ub represent ubiquitination.

Figure 3

LncRNA action downstream of IFN signaling. Type I and III IFNs stimulate JAK/STAT pathways that induce the expression of ISGs. LncRNAs can affect ISG transcription (IVRPIE, NRAV, TSPOAP1-AS1); sponge miRNAs that downregulate ISG translation (Lnc-ISG20, IFITM4P); and attenuate STAT1-mediated gene expression (LUCAT1). LncRNA-155 and its product miR-155 have distinct roles in innate immunity regulation; miR-155 is considered to attenuate SOCS1-dependent JAK/STAT pathways inhibition, while LncRNA-155 stimulates INFB expression and blocks PTP1B action. Red arrows represent the activation of ISG upregulating pathways by lncRNAs; blue arrows represent inhibitory lncRNA action; green arrows represent signaling events causing ISG expression; light blue ellipses represent lncRNA interacting proteins/factors; red ellipses represent ISG/IFN upregulating proteins; dark blue ellipses—ISG inhibiting factors; miRNAs are depicted in blue; mRNAs are depicted in red and Ub represent ubiquitination.