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Review
.2020 Jul 16;9(7):1701.
doi: 10.3390/cells9071701.

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

Affiliations
Review

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

Takuya Uehata et al. Cells..

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.

Keywords: RIG-I-like receptors; RNA binding proteins; RNA virus; Regnase-1; Toll-like receptors; cytokines; mRNA decay; type I interferons.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The role of type I IFNs between innate immunity and T cell-mediated antiviral immunity. Upon viral infection, direct recognition of viral nucleic acids by dendritic cells (DCs) and danger signals from infected cells can induce antiviral responses. When activated, DCs undergo maturation to express costimulatory molecules, such as CD86. In draining lymph nodes, these DCs act as antigen-presenting cells presenting viral antigens to CD8 T cells through dependence on MHC-I. Simultaneously, type I IFNs (e.g., IFNα and IFNβ) produced by innate immune and infected cells further activate CTLs and NK cells to enhance cytotoxicity. Type I IFNs also act on infected cells and neighboring cells, in an autocrine and paracrine fashion, which promotes apoptosis of infected cells and renders uninfected cells resistant to viral infection. CTL; cytotoxic T lymphocyte.
Figure 2
Figure 2
RNA sensing mechanisms. RNA sensing mechanisms are composed of endosomal and cytoplasmic sensors. (a) Endosomal RNA sensors, TLR3 and TLR7/8, recognize dsRNA and ssRNA, respectively. TLR3 activates the TRIF-dependent pathway to activate IRF3/7, NF-κB, and AP-1. In contrast, TLR7/8 triggers the MyD88-dependent pathway and leads to the activation of NF-κB and AP-1, and simultaneously activates IRF5/7 to induce type I IFN genes. In addition to recognizing ssRNA, TLR7 and TLR8 can be activated by guanosine and uridine residues, respectively. Uridine molecules for TLR8 are degraded products generated by RNaseT2 and RNase2, although it remains unknown how guanosine residues are generated. The engagement of both ligands achieves maximum activation of TLR7/8. (b) RIG-I and MDA5 are central RNA sensors that localize to the cytosol, and both harbor the N-terminal tandem caspase-recruitment domains (CARDs) and helicase domains. After binding to dsRNA, these RNA sensors undergo oligomerization along dsRNA structures, which then activates MAVS through CARD–CARD interaction. These sequential events then activate IRF3/7 along with NF-κB to induce IFN-I responses. (c) Alternative RNA sensing is mediated by RNA receptors whose expressions are induced by RLR activation. OAS1 generates 2′-5′-oligoadenylate that activates RNase L, which promotes the degradation of dsRNAs. The resulting fragments of dsRNAs can also activate the RIG-I-like receptor (RLR)-sensing pathway. PKR is a Ser/Thr protein kinase that is present in the unphosphorylated form. After binding to dsRNA, PKR undergoes autophosphorylation and dimerization, which inhibits viral protein synthesis and induces the IFN-I response. IFIT1 recognizes capped RNA with 5’-triphosphate ends, which can block the translation of viral RNA. U, uridine; G, guanosine; IFN-I, type I interferon; CARD, caspase activation recruitment domain.
Figure 3
Figure 3
Mechanisms where endogenous RNAs can be recognized by RNA sensors. IRAlu elements can form dsRNA as self. Adenosine deaminase (ADAR) 1 destabilizes dsRNA structures via its A-to-I editing, which results in an escape from the recognition of host RNA sensors. mtDNA also potentially generates dsRNAs. The degradosome localized to the mitochondria can prevent dsRNA formation by limiting the accumulation of transcripts derived from mtDNA. In both cases, the abnormal formation of dsRNA can lead to aberrant type I IFN (IFN-I) responses. IRAlu; inverted repeat Alu, mtDNA; mitochondrial DNA.
Figure 4
Figure 4
Posttranscriptional mechanisms by RNA-binding proteins (RBPs) regulating mRNA stability. (a) TTP, AUF1, and KSRP are representative RBPs that promote mRNA decay by binding to an AU-rich element (ARE) present in 3′UTR. HuR is an RBP that inhibits mRNA decay by competing for ARE sites. (b) TTP promotes mRNA decay through the recruitment of the deadenylation complex, CCR4-NOT, and Dcp1 and Dcp2 decapping enzymes. This can be suppressed by MK2-mediated phosphorylation of TTP, which is induced downstream of p38 mitogen-activated protein kinase (MAPK) in response to TLR4 activation. The phosphorylated form of TTP is sequestered by the 14-3-3 protein, which results in enhanced stability of target mRNAs. (c) Regnase-1 and Roquin are representative RBPs that recognize stem-loop structures present in 3′UTR. There are two distinct mRNA decay mechanisms: (1) Endonucleolytic cleavage by endonucleases and (2) mRNA decay induced by recruitment of the deadenylation complex and decapping enzymes. (1) Regnase-1 is an endonuclease that recognizes the stem-loop structure, and cooperatively promotes cleavage of target mRNA with UPF1. However, this process can be blocked by Arid5a. In addition, Regnase-1-mediated mRNA decay is also regulated when this protein undergoes IKK-mediated phosphorylation and subsequent proteasomal degradation. (d) Malt1 is a key component of the T cell receptor (TCR)-signaling pathway that contributes to posttranscriptional mechanisms. After the engagement of TCR, Malt1 is activated as a component of the Card11-Bcl10-Malt1 (CBM) complex downstream of PKCθ. Malt1 also acts on a set of substrates for its paracaspase, including Regnase-1, N4BP1, and Roquin. Malt1-mediated cleavage deactivates these proteins.
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