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Intracellular Sensing of Viral Genomes and Viral Evasion Hyun-Cheol Lee1,2, Kiramage Chathuranga 1 and Jong-Soo Lee1

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Intracellular Sensing of Viral Genomes and Viral Evasion Hyun-Cheol Lee1,2, Kiramage Chathuranga 1 and Jong-Soo Lee1 Lee et al. Experimental & Molecular Medicine (2019) 51:153 https://doi.org/10.1038/s12276-019-0299-y Experimental & Molecular Medicine REVIEW ARTICLE Open Access Intracellular sensing of viral genomes and viral evasion Hyun-Cheol Lee1,2, Kiramage Chathuranga 1 and Jong-Soo Lee1 Abstract During viral infection, virus-derived cytosolic nucleic acids are recognized by host intracellular specific sensors. The efficacy of this recognition system is crucial for triggering innate host defenses, which then stimulate more specific adaptive immune responses against the virus. Recent studies show that signal transduction pathways activated by sensing proteins are positively or negatively regulated by many modulators to maintain host immune homeostasis. However, viruses have evolved several strategies to counteract/evade host immune reactions. These systems involve viral proteins that interact with host sensor proteins and prevent them from detecting the viral genome or from initiating immune signaling. In this review, we discuss key regulators of cytosolic sensor proteins and viral proteins based on experimental evidence. Introduction Toll-like receptors, C-type lectin receptors, retinoic acid- Viral infection is a major threat to human and animal inducible gene-I (RIG-I)-like receptors (RLRs), health worldwide. Acute and chronic infections cause nucleotide-binding oligomerization domain (NOD)-like 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; many economic and social problems. Over the past few receptors, and cytosolic DNA sensors such as cyclic decades, the field of molecular cell biology has con- GMP-AMP synthetase1. Sensing of viral PAMPs by PRRs tributed to our knowledge of both viruses and the host triggers signaling cascades via adapter proteins such as innate immune reactions that they trigger. In particular, mitochondrial antiviral signaling protein (MAVS) or sti- we now understand how host cells recognize invading mulator of interferon genes (STING), ultimately leading viruses and how the antiviral signaling cascade is to the production of host defense molecules such as type I regulated. and III interferons (IFNs), proinflammatory cytokines, Host innate immunity is the first line of defense against and chemokines2. Secreted IFNs and cytokines enhance viral infection. Efficient and rapid detection of invading innate immune responses via autocrine and paracrine viruses, coupled with mechanisms that distinguish viral mechanisms and induce expression of interferon- components from host components, is a critical factor. stimulated genes (ISGs) that inhibit viral replication and Upon viral infection, virus-derived pathogen-associated spread3. Secreted cytokines and chemokines are also cri- molecular patterns (PAMPs), such as viral capsid proteins, tical for inducing effective adaptive and memory immune surface glycoproteins, and the viral genome, are recog- responses. nized by host pattern recognition receptors (PRRs). There Nonetheless, excessive production of IFNs and pro- are several types of PRRs, which are identified according longed inflammatory responses triggered by uncontrolled to cellular localization and ligand specificity; these include PRR signaling can have deleterious effects on the host by promoting the development of autoimmune disorders, allergies, and other immunopathologies4. In contrast, Correspondence: Jong-Soo Lee ([email protected]) weak or ineffective PRR signal transduction exacerbates 1 College of Veterinary Medicine, Chungnam National University, Daejeon the severity of viral disease. Therefore, PRR-mediated 34134, Korea 2Central Research Institute, Komipharm International Co., Ltd, Shiheung 15094, signal transduction must be tightly regulated (either Korea © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Lee et al. Experimental & Molecular Medicine (2019) 51:153 Page 2 of 13 positively or negatively) to maintain host immune Table 1 Summary of RNA and DNA viruses and ligand homeostasis5. recognition by PRRs In addition, viruses have evolved several strategies to PRR Agonist Representative virus avoid detection of host antiviral immune responses; these range from interruption of viral sensors to manipulation RIG-I 5' ppp dsRNA SeV, NDV, RSV, MV, VSV, IAV, EBOV, JEV, 6 of molecules within signaling cascades . For example, the short dsRNA HCV, WNV, DENV, Rotavirus, Vaccinia fi viral genome harbors structures that mask speci c 5' ppp ssRNA virus, Adenovirus, Rift Valley fever virus, molecular motifs recognized by cytosolic sensors. Some AU-rich 3' UTR Lassa virus, Nipha virus, Rabies virus, viral proteins inhibit host sensor molecules by cleaving or RNase L cleavage Influenza B virus mediating degradation of signaling molecules or by products fi interfering with post-translational modi cations (PTMs) Circular viral RNA 6 of sensors . From the perspective of the virus, these pU/UC HCV actions during the early phase of invasion are critical for genomic RNA successful infection. MDA5 Long dsRNA ECMV, MV, WNV, SeV, DENV, MHV, HCV, Here, we summarize recent evidence regarding inter- RNase L cleavage PIV5, EV, Murine norovirus-1, Rabies actions between key intracellular sensors, viral RNA/ products virus, Saffold virus, Rotavirus, DNA, and molecules that regulate efficient IFN responses AU-rich motifs Adenoviruses, Theiler’s virus or maintenance of host immune homeostasis. Further- more, we describe recent advances in our knowledge LGP2 dsRNA ECMV, VSV, HCV, Poliovirus about viral evasion of host cytosolic sensors, focusing on cGAS RNA:DNA HSV-1, MHV68, Adenovirus interactions between cytosolic sensors and specific viral intermediate proteins. dsDNA ssDNA Host viral RNA sensors and viral evasion Mitochondrial DNA mechanisms IFI16 dsDNA HSV-1, HCMV, KSHV, EBV Upon viral infection, the viral genome is released into ssDNA the cytoplasm to initiate viral protein biosynthesis. During AIM2 dsDNA MCMV, Vaccina virus this step, conserved molecular structures such as tripho- sphates and double-stranded (ds)RNA act as PAMPs that dsRNA double-stranded RNA, ssRNA single-stranded RNA, UTR untranslated dsDNA ssDNA are recognized by sensors in the host cell cytosol (Table region, double-stranded DNA, single-stranded DNA 1). The host innate immune system includes receptors, called PRRs, that distinguish the viral genome from the recognizes 5′ tri- or di-phosphorylated dsRNA, the AU- host genome. To achieve this, RLRs comprising RIG-I, rich 3′untranslated region (UTR), RNase L cleavage pro- melanoma differentiation-associated protein 5 (MDA5), ducts, and circular viral RNA9,10. RIG-I detects the gen- laboratory of genetics and physiology 2 (LGP2), and other omes of viruses such as vesicular stomatitis virus (VSV), sensors such as NACHT, LRR, PYD domain-containing influenza A virus (IAV), Sendai virus (SeV), Newcastle protein 3 (NLRP3), and nucleotide-binding oligomeriza- disease virus (NDV), respiratory syncytial virus (RSV), tion domain-containing protein 2, act as intracellular viral hepatitis C virus (HCV), and Japanese encephalitis virus – RNA sensors7. These proteins bind to viral RNA in the (JEV)10 12. In addition, some DNA viruses such as vac- cell cytoplasm via RNA binding motifs, after which their cinia virus and Herpes simplex virus (HSV)9 and bacteria signaling domain interacts with downstream adapter such as Listeria monocytogenes generate RNA that is then molecules, resulting in the activation of signaling cas- targeted by RIG-I13. Structurally, RIG-I comprises two N- cades. The reactions are triggered as an immediate terminal caspase activation and recruitment domains response to infection by RNA viruses and result in the (CARDs), two helicase domains (Hel-1 and Hel-2), and a production of type I IFNs, proinflammatory cytokines, C-terminal repressor domain (RD)14. In the resting state, and chemokines2,8. However, RNA viruses possess an RIG-I is autoinhibited by its own RD. In response to virus arsenal of mechanisms to attenuate innate immune invasion, RIG-I recognizes viral RNA via its two compo- responses. Below, we describe the activation and regula- nents: the RD and helicase domain. The RD facilitates tion processes of major sensor molecules and mechanisms viral RNA recognition through its strong affinity for the 5′ by which viruses evade them. end triphosphate, and the positively charged pocket structure of the RD interacts with the 5′ end of viral RIG-I RNA15,16. The helicase domain binds to dsRNA and RIG-I, which belongs to the DExD/H box RNA helicase mediates a conformational change that allows ATP family, is an intracellular sensor of viral RNA. RIG-I binding to activate RIG-I15,16. This conformational change Official journal
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