RNA Recognition and Immunity—Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms

Abstract

RNA acts as an immunostimulatory molecule in the innate immune system to activate nucleic acid sensors. It functions as an intermediate, conveying genetic information to control inflammatory responses. A key mechanism for RNA sensing is discriminating self from non-self nucleic acids to initiate antiviral responses reliably, including the expression of type I interferon (IFN) and IFN-stimulated genes. Another important aspect of the RNA-mediated inflammatory response is posttranscriptional regulation of gene expression, where RNA-binding proteins (RBPs) have essential roles in various RNA metabolisms, including splicing, nuclear export, modification, and translation and mRNA degradation. Recent evidence suggests that the control of mRNA stability is closely involved in signal transduction and orchestrates immune responses. In this study, we review the current understanding of how RNA is sensed by host RNA sensing machinery and discuss self/non-self-discrimination in innate immunity focusing on mammalian species. Finally, we discuss how posttranscriptional regulation by RBPs shape immune reactions.

Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

“…When dsRNA binds to RIG-1 or MDA5, oligomerization of the RNA sensors occurs which leads to activation of MAVS. As a result, IRF3/7 along with NF-κB gets activated and Interferon production is induced ( Uehata and Takeuchi, 2020 ).…”

Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses

“…The common ligands of TLR3 exist on poly(I:C), dsRNA viruses (e.g., rotavirus (RV), respiratory syncytial virus (RSV), murine cytomegalovirus (MCMV)), and single-stranded RNA (ssRNA) virus (e.g., West Nile virus (WNV)) (Alexopoulou et al, 2001;Topping and Kelly, 2019;Uehata and Takeuchi, 2020). A recent report showed that endothelial TLR3 could also detect extracellular dsRNA that is secreted from highly metastatic tumors (Tavora et al, 2020).…”

Type I IFN Signaling Limits Hemorrhage-Like Disease After Infection With Japanese Encephalitis Virus Through Modulating A Prerequisite Infection of CD11b+Ly-6C+ Monocytes

“…This implies that the ablation of the IFN-I signal did not induce blunted IFN-I production after JEV footpad inoculation and, rather, the magnitude of IFN-I (IFN-α/β) expression seemed to follow the degree of JEV replication because the replication of JEV was coupled to the expression levels of IFN-α/β. IFN-I (IFN-α/β) binds to a heterodimeric receptor (IFNAR) and mediates downstream pleiotropic functions of the canonical JAK-STAT signaling pathway [23,24]. This stimulation results in the induction of antiviral ISGs, induction of cell surface and cytosolic PRRs in antigenpresenting cells, and the regulation of cytokine and chemokine production [19].…”

“…Indeed, the critical role of IFN-I and its transcription factors (IRF3, IRF5, and IRF7) has been described in avivirus infection in vivo including WNV and DenV, but not JEV [20][21][22]. IFN-I secreted from infected cells binds in an autocrine and paracrine manner to a heterodimeric IFN-α/β receptor (IFNAR) on the surface of cells and mediates pleiotropic effects via canonical Janus kinase (JAK)-signal transducer and activator of transcription (STAT1/2) signaling pathway [23,24]. Phosphorylated STAT1/2 heterodimer associates with IRF-9 to form ISGF3 complexes, which results in the induction of antiviral IFN-stimulated genes (ISGs, e.g., Mx1, OAS, PKR, ISG49[IFIT3], ISG54[IFIT2], ISG56[IFIT1]) through its nuclear translocation and binding to IFN-stimulated responsive elements [19].…”