Infection of cells by microorganisms activates the inflammatory response. The initial sensing of infection is mediated by innate pattern recognition receptors (PRRs), which include Toll-like ...receptors, RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors. The intracellular signaling cascades triggered by these PRRs lead to transcriptional expression of inflammatory mediators that coordinate the elimination of pathogens and infected cells. However, aberrant activation of this system leads to immunodeficiency, septic shock, or induction of autoimmunity. In this Review, we discuss the role of PRRs, their signaling pathways, and how they control inflammatory responses.
Innate immunity to virus infection Takeuchi, Osamu; Akira, Shizuo
Immunological reviews,
January 2009, Volume:
227, Issue:
1
Journal Article
Peer reviewed
Open access
The innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. Three classes of receptors, designated retinoic acid-inducible gene ...I (RIG-I)-like receptors (RLRs), Toll-like receptors (TLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs), sense viral components, such as double-stranded RNA (dsRNA), single-stranded RNA, and DNA. RLRs and TLRs play essential roles in the production of type I interferons (IFNs) and proinflammatory cytokines in cell type-specific manners. While the RLRs play essential roles in the recognition of RNA viruses in various cells, plasmacytoid dendritic cells utilize TLRs for detecting virus invasion. NLRs play a role in the production of mature interleukin-1β to dsRNA stimulation. Activation of innate immune cells is critical for mounting adaptive immune responses. In this review, we discuss recent advances in our understanding of the mechanisms of viral RNA recognition by these different types of receptors and its relation to acquired immune responses.
The activation of inflammatory cells is controlled at transcriptional and posttranscriptional levels. Posttranscriptional regulation modifies mRNA stability and translation, allowing for elaborate ...control of proteins required for inflammation, such as proinflammatory cytokines, prostaglandin synthases, cell surface co‐stimulatory molecules, and even transcriptional modifiers. Such regulation is important for coordinating the initiation and resolution of inflammation, and is mediated by a set of RNA‐binding proteins (RBPs), including Regnase‐1, Roquin, Tristetraprolin (TTP), and AU‐rich elements/poly(U)‐binding/degradation factor 1 (AUF1). Among these, Regnase‐1, also known as Zc3h12a and Monocyte chemotactic protein‐1‐induced protein‐1 (MCPIP1), acts as an endoribonuclease responsible for the degradation of mRNAs involved in inflammatory responses. Conversely, the RBPs Roquin and TTP trigger exonucleolytic degradation of mRNAs by recruiting the CCR4‐NOT deadenylase complex. Regnase‐1 specifically recognizes stem‐loop structures present in 3′‐untranslated regions of cytokine mRNAs, and directly degrades the mRNAs in a translation‐ and ATP‐dependent RNA helicase upframeshift 1 (UPF1)‐dependent manner that is reminiscent of nonsense‐mediated decay. Regnase‐1 regulates the activation of innate and acquired immune cells, and is critical for maintaining immune homeostasis as well as preventing over‐activation of the immune system under inflammatory conditions. Furthermore, recent studies have revealed that Regnase‐1 and its family members are involved not only in immunity but also in various biological processes. In this article, I review molecular mechanisms of Regnase‐1‐mediated mRNA decay and its physiological roles. WIREs RNA 2018, 9:e1449. doi: 10.1002/wrna.1449
This article is categorized under:
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA in Disease and Development > RNA in Disease
Regnase‐1/MCPIP1 is an endoribonuclease that degrades a set of mRNAs in a translation dependent manner by interacting with UPF1. Regnase‐1 recognizes mRNAs harboring a stem‐loop structure in the 3' untranslated region, and regulates various biological processes such as innate and adaptive immunity, as well as development, cancer and metabolism.
The innate immune system deploys a variety of pattern-recognition receptors (PRRs) which include Toll-like receptors (TLRs), RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors to ...detect the invasion of pathogens and initiate protective responses. The intercellular and intracellular orchestration of signals from different PRRs, their endogenous or microbial ligands and accessory molecules determine the stimulatory or inhibitory responses. Progressing over the last two decades, considerable research on the molecular mechanisms underlying host-pathogen interactions has led to a paradigm shift of our understanding of TLR signaling in the innate immune system. Given that a significant amount of evidence implicates TLRs in the pathogenesis of immune diseases and cancer, and their activation occurs early in the inflammatory cascade, they are attractive targets for novel therapeutic agents. In this review, we discuss the recent advances in TLR signaling cross talks and the mechanism of pathogen recognition with special emphasis on the role of TLRs in tumor immunity and TLR-targeted therapeutics.
The central dogma of molecular biology entails that genetic information is transferred from nucleic acid to proteins. Notwithstanding retro-transcribing genetic elements, DNA is transcribed to RNA ...which in turn is translated into proteins. Recent advancements have shown that each stage is regulated to control protein abundances for a variety of essential physiological processes. In this regard, mRNA regulation is essential in fine-tuning or calibrating protein abundances. In this review, we would like to discuss one of several mRNA-intrinsic features of mRNA regulation that has been gaining traction of recent—codon bias and optimality. Specifically, we address the effects of codon bias with regard to codon optimality in several biological processes centred on translation, such as mRNA stability and protein folding among others. Finally, we examine how different organisms or cell types, through this system, are able to coordinate physiological pathways to respond to a variety of stress or growth conditions.
Cytokines are critical mediators of inflammation and host immune defense. Cytokine production is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional damping of ...inflammatory mRNAs is mediated by a set of RNA binding proteins (RBPs) interacting with cis-elements, such as AU-rich elements (ARE) and stem-loop structures. Whereas ARE-binding proteins such as tristetraprolin and a stem-loop recognizing protein, Roquin, downregulate cytokine mRNA abundance by recruiting a CCR4-NOT deadenylase complex, another stem-loop RBP, Regnase-1, acts as an endoribonuclease, directly degrading target cytokine mRNAs. These RBPs control translation-active or -inactive mRNAs in distinct intracellular locations. The presence of various RBPs regulating mRNAs in distinct locations enables elaborate control of cytokines under inflammatory conditions. Dysregulation of cytokine mRNA decay leads to pathologies such as the development of autoimmune diseases or impaired activation of immune responses. Here we review current knowledge about the post-transcriptional regulation of immune responses by RBPs and the importance of their alteration during inflammatory pathology and autoimmunity.
Dynamic changes in gene expression are key factors in the development and activation of immune cells. RNA metabolism is one of the critical steps for the control of gene expression. Together with ...transcriptional regulation, mRNA decay by specific ribonucleases (RNases) plays a vital role in shaping gene expression. In addition to the canonical exoribonuclease‐mediated mRNA degradation through the recognition of cis‐elements in mRNA 3′ untranslated regions by RNA‐binding proteins (RBPs), endoribonucleases are involved in the control of mRNAs in immune cells. In this review, we gleam insights on how Regnase‐1, an endoribonuclease necessary for regulating immune cell activation and maintenance of immune homeostasis, degrades RNAs involved in immune cell activation. Additionally, we provide insights on recent studies which uncover the role of Regnase‐1–related RNases, including Regnase‐2, Regnase‐3, and Regnase‐4, as well as N4BP1 and KHNYN, in immune regulation and antiviral immunity. As the dysregulation of immune mRNA decay leads to pathologies such as autoimmune diseases or impaired activation of immune responses, RNases are deemed as essential components of regulatory feedback mechanisms that modulate inflammation. Given the critical role of RNases in autoimmunity, RNases can be perceived as emerging targets in the development of novel therapeutics.
The innate immune system plays critical roles in recognizing viral infections and evoking initial anti-viral responses. Nucleotides from RNA viruses are recognized by retinoic acid-inducible gene I ...(RIG-I)-like helicases (RLHs) and Toll-like receptors (TLRs), and the recognition triggers signaling cascades that induce anti-viral mediators such as type I interferons (IFNs) and pro-inflammatory cytokines. The RLH signaling pathways play essential roles in the recognition of RNA viruses in various cells, with the exception of plasmacytoid dendritic cells (pDCs). However, TLRs are important for the production of type I IFNs in pDCs but not in other cell types. The contributions of RLHs and TLRs to the production of type I IFNs in response to RNA viruses vary depending on the route of infection. Specifically, local infections induce IFNs through RLHs but not TLRs, whereas systemic infections strongly stimulate TLRs in pDCs. In this review, we discuss recent advances toward clarifying the signaling pathways activated by RLHs and TLRs.
Innate immunity is one of the most ancient and conserved aspect of the immune system. It is responsible for an anti-infective response and has been intrinsically linked to the generation of ...inflammation. While the inflammatory response entails signaling to the adaptive immune system, it can be self-perpetuating and over-exaggerated, resulting in deleterious consequences, including cytokine storm, sepsis, and the development of inflammatory and autoimmune diseases. Cytokines are the defining features of the immune system. They are critical to mediation of inflammation and host immune defense, and are tightly regulated at several levels, including transcriptional and post-transcriptional levels. Recently, the role of post-transcriptional regulation in fine-tuning cytokine expression has become more appreciated. This interest has advanced our understanding of how various mechanisms are integrated and regulated to determine the amount of cytokine production in cells during inflammatory responses. Here, we would like to review how innate immunity recognizes and responds to pathogens by pattern-recognition receptors, and the molecular mechanisms regulating inflammatory responses, with a focus on the post-transcriptional regulations of inflammatory mediators by RNA-binding proteins, especially Regnase-1. Finally, we will discuss the regulatory mechanisms of Regnase-1 and highlight therapeutic strategies based on targeting Regnase-1 activity and its turnover as potential treatment options for chronic and autoimmune diseases.
Group 2 innate lymphoid cells (ILC2s) are unique in their ability to produce low levels of type 2 cytokines at steady state, and their production capacity is dramatically increased upon stimulation ...with IL-33. However, it is unknown how constitutive cytokine production is regulated in the steady state. Here, we found that tristetraprolin (TTP/Zfp36), an RNA-binding protein that induces mRNA degradation, was highly expressed in naive ILC2s and was downregulated following IL-33 stimulation. In ILC2s from Zfp36-/- mice, constitutive IL-5 production was elevated owing to the stabilization of its mRNA and resulted in an increased number of eosinophils in the intestine. Luciferase assay demonstrated that TTP directly regulates Il5 mRNA stability, and overexpression of TTP markedly suppressed IL-5 production by ILC2s, even under IL-33 stimulation. Collectively, TTP-mediated posttranscriptional regulation acts as a deterrent of excessive cytokine production in steady-state ILC2s to maintain body homeostasis, and downregulation of TTP may contribute to massive cytokine production under IL-33 stimulation.
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