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Takashi Fujita - One of the best experts on this subject based on the ideXlab platform.
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Aberrant Activation of RIG-I–Like Receptors and Autoimmune Diseases
Chronic Inflammation, 2016Co-Authors: Hiroki Kato, Takashi FujitaAbstract:RIG-I–like Receptors (RLRs) are known as viral RNA sensors that trigger the antiviral interferon (IFN) response by the recognition of the nonself signatures in viral RNAs, including 5’ triphosphate structure and double-strand. Self-RNAs generally escape their recognition by several modifications such as 5’ cap; however, it has recently been shown that endogenous RNAs without an adenosine deaminase ADAR1-dependent modification aberrantly activate RLR signalling and lead to severe IFN signature, resulting in autoimmune disorders. Also gain-of-function mutations of RLRs have been found in patients with autoimmune diseases. We herein provide a recent overview of the RLR-mediated antiviral IFN response and autoimmunity and discuss how atypical activation of RLRs triggers autoimmune diseases.
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Cytoplasmic Viral RNA Sensors: RIG-I-like Receptors
Encyclopedia of Immunobiology, 2016Co-Authors: Hiroki Kato, Takashi FujitaAbstract:The interferon (IFN) response is a powerful system that was evolutionarily acquired by vertebrates including mammals to protect against viral infection. The cytoplasmic RNA helicases, RIG-I-like Receptors (RLRs), were discovered in 2004 as viral sensors that trigger the antiviral IFN response by recognizing the nonself signatures of viral RNAs. The mechanisms underlying the recognition of viral RNAs and signal transduction leading to the production of type I IFN have been intensively studied following the discovery of RLRs. Moreover, a dysregulation in the expression of RLR or aberrant RLR signaling has been implicated in the development of a number of autoimmune diseases. We herein provide an overview of recent advances in RLR research and discussed future directions.
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RIG-I-like Receptors and autoimmune diseases
Current Opinion in Immunology, 2015Co-Authors: Hiroki Kato, Takashi FujitaAbstract:Type I interferon (IFN) plays an essential role in antiviral innate immune responses and also in adaptive immune responses. Defects in the production of IFN markedly increase susceptibility to viral invasion and attenuate the acquired immunity. Recently an increased expression of type I IFN, also termed IFN signature, has been reported in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi–Goutieres syndrome (AGS). The evidence clearly shows that the initiation and termination of IFN production should be tightly controlled. RIG-I-like Receptors (RLRs) are viral RNA sensors and are essential for type I IFN induction. We herein summarize recent reports on RLR mutations in patients and MDA5 mutant mice, and discuss possible mechanisms by which aberrant activation of RLRs can cause autoimmunity.
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Viral RNA detection by RIG-I-like Receptors
Current Opinion in Immunology, 2015Co-Authors: Mitsutoshi Yoneyama, Michihiko Jogi, Teppei Akaboshi, Koji Onomoto, Takashi FujitaAbstract:In higher vertebrates, recognition of the non-self signature of invading viruses by genome-encoded pattern recognition Receptors initiates antiviral innate immunity. Retinoic acid-inducible gene I (RIG-I)-like Receptors (RLRs) detect viral RNA as a non-self pattern in the cytoplasm and activate downstream signaling. Detection of viral RNA also activates stress responses resulting in stress granule-like aggregates, which facilitate RLR-mediated antiviral immunity. Among the three RLR family members RIG-I and melanoma differentiation-associated gene 5 (MDA5) recognize distinct viral RNA species with differential molecular machinery and activate signaling through mitochondrial antiviral signaling (MAVS, also known as IPS-1/VISA/Cardif), which leads to the expression of cytokines including type I and III interferons (IFNs) to restrict viral propagation. In this review, we summarize recent knowledge regarding RNA recognition and signal transduction by RLRs and MAVS/IPS-1.
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Sensing viral invasion by RIG-I like Receptors.
Current Opinion in Microbiology, 2014Co-Authors: Hiroki Kato, Takashi FujitaAbstract:Cellular responses to pathogen invasion are crucial for maintaining cell homeostasis and survival. The interferon (IFN) system is one of the most effective cellular responses to viral intrusion in mammals. Viral recognition by innate immune sensors activates the antiviral IFN system. Retinoic acid-inducible gene I (RIG-I) like Receptors (RLRs) are DExD/H box RNA helicases that sense viral invasion. RLRs recognize cytoplasmic viral RNAs and trigger antiviral responses, resulting in production of type I IFN and inflammatory cytokines. Unique and common sensing mechanisms among RLRs have been reported. In this review, recent progress in the understanding of antiviral responses by RLRs is summarized and discussed.
Daisy W. Leung - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of Non-segmented Negative Sense RNA Viral Antagonism of Host RIG-I-like Receptors.
Journal of molecular biology, 2019Co-Authors: Daisy W. LeungAbstract:The pattern recognition Receptors RIG-I-like Receptors (RLRs) are critical molecules for cytosolic viral recognition and for subsequent activation of type I interferon production. The interferon signaling pathway plays a key role in viral detection and generating antiviral responses. Among the many pathogens, the non-segmented negative sense RNA viruses target the RLR pathway using a variety of mechanisms. Here, I review the current state of knowledge on the molecular mechanisms that allow non-segmented negative sense RNA virus recognition and antagonism of RLRs.
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Mechanisms of Non-segmented Negative Sense RNA Viral Antagonism of Host RIG-I-like Receptors
Journal of Molecular Biology, 2019Co-Authors: Daisy W. LeungAbstract:Abstract The pattern recognition Receptors RIG-I-like Receptors (RLRs) are critical molecules for cytosolic viral recognition and for subsequent activation of Type I interferon (IFN) production. The IFN signaling pathway plays a key role in viral detection and generating antiviral responses. Among the many pathogens, the non-segmented negative sense RNA viruses (NNSVs) target the RLR pathway using a variety of mechanisms. Here, I review the current state of knowledge on the molecular mechanisms that allow NNSV recognition and antagonism of RLRs.
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Structural insights into RNA recognition and activation of RIG-I-like Receptors
Current Opinion in Structural Biology, 2012Co-Authors: Daisy W. Leung, Gaya K. AmarasingheAbstract:RIG-I like Receptors (RLR) that recognize non-self RNA play critical roles in activating host innate immune pathways in response to viral infections. Not surprisingly, RLRs and their associated signaling networks are also targeted by numerous antagonists that facilitate viral pathogenesis. Although the role of RLRs in orchestrating antiviral signaling has been recognized for some time, our knowledge of the complex regulatory mechanisms that control signaling through these key molecules is incomplete. A series of recent structural studies shed new light into the structural basis for dsRNA recognition and activation of RLRs. Collectively, these studies suggest that the repression of RLRs is facilitated by a cis element that makes multiple contacts with domains within the helicase and that RNA binding initiated by the C-terminal RNA binding domain is important for ATP hydrolysis and release of the CARD domain containing signaling module from the repressed conformation. These studies also highlight potential differences between RIG-I and MDA5, two RLR members. Together with previous studies, these new results bring us a step closer to uncovering the complex regulatory process of a key protein that protects host cells from invading pathogens.
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Molecular mechanisms of viral inhibitors of RIG-I-like Receptors
Trends in Microbiology, 2012Co-Authors: Daisy W. Leung, Christopher F. Basler, Gaya K. AmarasingheAbstract:Activation of innate immune signaling pathways through cytosolic RIG-I-like Receptors (RLR) is a crucial response that is antagonized by many viruses. A variety of RNA-related pathogen-associated molecular patterns (PAMPS) have been identified and their role in RLR activation has been examined. Recent studies suggest that several virus-encoded components that antagonize RLR signaling interact with and inhibit the interferon (IFN)-α/β activation pathway using both RNA-dependent and RNA-independent mechanisms. The structural basis for these RLR inhibitory mechanisms, as well as the multifunctional nature of viral RLR antagonists, is reviewed in the context of recent biochemical and structural studies.
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Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35
Nature Structural & Molecular Biology, 2010Co-Authors: Daisy W. Leung, Kathleen C Prins, Dominika M Borek, Mina Farahbakhsh, Joann M Tufariello, Parameshwaran Ramanan, Jay C Nix, Luke A Helgeson, Zbyszek Otwinowski, Richard B HonzatkoAbstract:Ebola viral protein 35 (VP35), encoded by the highly pathogenic Ebola virus, facilitates host immune evasion by antagonizing antiviral signaling pathways, including those initiated by RIG-I–like Receptors. Here we report the crystal structure of the Ebola VP35 interferon inhibitory domain (IID) bound to short double-stranded RNA (dsRNA), which together with in vivo results reveals how VP35-dsRNA interactions contribute to immune evasion. Conserved basic residues in VP35 IID recognize the dsRNA backbone, whereas the dsRNA blunt ends are 'end-capped' by a pocket of hydrophobic residues that mimic RIG-I–like receptor recognition of blunt-end dsRNA. Residues critical for RNA binding are also important for interferon inhibition in vivo but not for viral polymerase cofactor function of VP35. These results suggest that simultaneous recognition of dsRNA backbone and blunt ends provides a mechanism by which Ebola VP35 antagonizes host dsRNA sensors and immune responses. The protein VP35 from Ebola virus contributes to immune evasion by antagonizing interferon signaling pathways. Now the crystal structure of the interferon inhibitory domain of VP35 bound to dsRNA indicates that VP35 sequesters the dsRNA ends, preventing them from being sensed by RIG-I-like Receptors and inhibiting immune responses.
Michael Gale - One of the best experts on this subject based on the ideXlab platform.
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Spatiotemporal dynamics of innate immune signaling via RIG-I–like Receptors
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Katharina Esser-nobis, Lauren D. Hatfield, Michael GaleAbstract:RIG-I, MDA5, and LGP2 comprise the RIG-I-like Receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition Receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.
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RIG-I-like Receptors direct inflammatory macrophage polarization against West Nile virus infection.
Nature communications, 2019Co-Authors: Amy E. L. Stone, Richard Green, Courtney Wilkins, Emily A. Hemann, Michael GaleAbstract:RIG-I-like Receptors (RLRs) RIG-I, MDA5, and LGP2, are vital pathogen recognition Receptors in the defense against RNA viruses. West Nile Virus (WNV) infections continue to grow in the US. Here, we use a systems biology approach to define the contributions of each RLR in the innate immune response to WNV. Genome-wide RNAseq and bioinformatics analyses of macrophages from mice lacking either RLR reveal that the RLRs drive distinct immune gene activation and response polarization to mediate an M1/inflammatory signature while suppressing the M2/wound healing phenotype. While LGP2 functions to modulate inflammatory signaling, RIG-I and MDA5 together are essential for M1 macrophage polarization in vivo and the control of WNV infection through potential downstream control of ATF4 and SMAD4 to regulate target gene expression for cell polarization. These analyses reveal the RLR-driven signature of macrophage polarization, innate immune protection, and immune programming against WNV infection.
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RIG-I-like Receptors Direct Inflammatory Macrophage Polarization against West Nile Virus Infection.
Nature Communications, 2019Co-Authors: Amy E. L. Stone, Richard Green, Courtney Wilkins, Emily A. Hemann, Michael GaleAbstract:RIG-I-like Receptors (RLRs) RIG-I, MDA5, and LGP2, are vital pathogen recognition Receptors in the defense against RNA viruses. West Nile Virus (WNV) infections continue to grow in the US. Here, we use a systems biology approach to define the contributions of each RLR in the innate immune response to WNV. Genome-wide RNAseq and bioinformatics analyses of macrophages from mice lacking either RLR reveal that the RLRs drive distinct immune gene activation and response polarization to mediate an M1/inflammatory signature while suppressing the M2/wound healing phenotype. While LGP2 functions to modulate inflammatory signaling, RIG-I and MDA5 together are essential for M1 macrophage polarization in vivo and the control of WNV infection through potential downstream control of ATF4 and SMAD4 to regulate target gene expression for cell polarization. These analyses reveal the RLR-driven signature of macrophage polarization, innate immune protection, and immune programming against WNV infection. RIG-I- like Receptors (RLRs) play an important role in immune defense against West Nile virus (WNV). Here, using a systems biology approach, the authors show that macrophage polarization to a proinflammatory M1 phenotype via RIG-I and MDA5 signaling is critical for innate immune control in WNV-infected mouse tissues.
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Role of RIG-I-like Receptors in innate immune sensing of Coxsackievirus B3 and encephalomyocarditis virus in murine macrophages and fibroblasts
bioRxiv, 2018Co-Authors: Esther Francisco, Mehul S. Suthar, Michael Gale, Amy B. Rosenfeld, Vincent R. RacanielloAbstract:Viral infections are sensed by pattern recognition Receptors that trigger an innate immune response through the expression of interferons (IFNs) and other cytokines. Most RNA viruses are sensed by the RIG-I like Receptors (RLR)s. The contributions of these Receptors to sensing viruses of the Picornaviridae family were investigated. Encephalomyocarditis virus (EMCV) and Coxsackievirus B3 (CVB3), picornaviruses of the Cardiovirus and Enterovirus genera, are detected by both MDA5 and RIG-I in bone marrow derived macrophages. In macrophages from wild type mice, type I IFN is produced early after infection; IFNbeta synthesis is reduced in the absence of each sensor, while IFNbeta production is reduced in the absence of MDA5. EMCV and CVB3 do not replicate in murine macrophages, and their detection is different in murine embryonic fibroblasts (MEFs), in which the viruses replicate to high titers. In MEFs RIG-I was essential for the expression of type I IFNs but contributes to increased yields of CVB3, while MDA5 inhibited CVB3 replication but in an IFN independent manner. These observations demonstrate that innate sensing of similar viruses by RLRs depends upon the cell type.
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Emerging complexity and new roles for the RIG-I-like Receptors in innate antiviral immunity
Virologica Sinica, 2015Co-Authors: John S. Errett, Michael GaleAbstract:Innate immunity is critical for the control of virus infection and operates to restrict viral susceptibility and direct antiviral immunity for protection from acute or chronic viral-associated diseases including cancer. RIG-I like Receptors (RLRs) are cytosolic RNA helicases that function as pathogen recognition Receptors to detect RNA pathogen associated molecular patterns (PAMPs) of virus infection. The RLRs include RIG-I, MDA5, and LGP2. They function to recognize and bind to PAMP motifs within viral RNA in a process that directs the RLR to trigger downstream signaling cascades that induce innate immunity that controls viral replication and spread. Products of RLR signaling also serve to modulate the adaptive immune response to infection. Recent studies have additionally connected RLRs to signaling cascades that impart inflammatory and apoptotic responses to virus infection. Viral evasion of RLR signaling supports viral outgrowth and pathogenesis, including the onset of viral-associated cancer.
Mitsutoshi Yoneyama - One of the best experts on this subject based on the ideXlab platform.
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Viral RNA detection by RIG-I-like Receptors
Current Opinion in Immunology, 2015Co-Authors: Mitsutoshi Yoneyama, Michihiko Jogi, Teppei Akaboshi, Koji Onomoto, Takashi FujitaAbstract:In higher vertebrates, recognition of the non-self signature of invading viruses by genome-encoded pattern recognition Receptors initiates antiviral innate immunity. Retinoic acid-inducible gene I (RIG-I)-like Receptors (RLRs) detect viral RNA as a non-self pattern in the cytoplasm and activate downstream signaling. Detection of viral RNA also activates stress responses resulting in stress granule-like aggregates, which facilitate RLR-mediated antiviral immunity. Among the three RLR family members RIG-I and melanoma differentiation-associated gene 5 (MDA5) recognize distinct viral RNA species with differential molecular machinery and activate signaling through mitochondrial antiviral signaling (MAVS, also known as IPS-1/VISA/Cardif), which leads to the expression of cytokines including type I and III interferons (IFNs) to restrict viral propagation. In this review, we summarize recent knowledge regarding RNA recognition and signal transduction by RLRs and MAVS/IPS-1.
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Cytoplasmic Sensing of Viral Double-Stranded RNA and Activation of Innate Immunity by RIG-I-like Receptors
Innate Immune Regulation and Cancer Immunotherapy, 2011Co-Authors: Mitsutoshi Yoneyama, Takashi FujitaAbstract:Innate antiviral reactions are induced within hours of a viral infection. These reactions are critical to the activation of adaptive immunity. The major innate antiviral reaction is that mediated by type I and III interferons (IFNs), which activate antiviral genes through cell surface Receptors, signal transducers, and transcription factors (Samuel. Clin Microbiol Rev 14:778–809, 2001; Theofilopoulos et al. Annu Rev Immunol 23:307–336, 2005; Uze and Monneron. Biochimie 89:729–734, 2007). Once the antiviral gene products establish an antiviral state, viral replication is selectively repressed. Efficient expression of IFN is observed in cells infected with viruses, suggesting that viral components produced during replication are detected by cellular sensors. A family of RNA helicases termed RIG-I-like Receptors (RLRs), including retinoic acid-inducible gene-I (RIG-I), melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), senses viral double-stranded (ds) RNA and triggers an antiviral program including the production of IFN (Kawai and Akira. Ann N Y Acad Sci 1143:1–20, 2008; Yoneyama and Fujita. Immunol Rev 227:54–65, 2009). We review here the structure and function of RLRs.
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rna recognition and signal transduction by rig i like Receptors
Immunological Reviews, 2009Co-Authors: Mitsutoshi Yoneyama, Takashi FujitaAbstract:Summary: Viral infection is detected by cellular sensor molecules as foreign nucleic acids and initiates innate antiviral responses, including the activation of proinflammatory cytokines and type I interferon (IFN). Recent identification of cytoplasmic viral sensors, such as retinoic acid-inducible gene-I-like Receptors (RLRs), highlights their significance in the induction of antiviral innate immunity. Moreover, it is intriguing to understand how they can discriminate endogenous RNA from foreign viral RNA and initiate signaling cascades leading to the induction of type I IFNs. This review focuses on the current understanding of the molecular machinery underlying RNA recognition and subsequent signal transduction by RLRs.
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Structural Mechanism of RNA Recognition by the RIG-I-like Receptors
Immunity, 2008Co-Authors: Mitsutoshi Yoneyama, Takashi FujitaAbstract:Cytoplasmic nonself RNA, such as that generated by invading viruses, is recognized by a family of sensory molecules termed RIG-I-like Receptors (RLRs). Here, we discuss the mechanism of the RLRs' sensing of nonself RNA. Our findings define three functional domains of RLRs and provide insights into how RLRs function as a molecular switch through interactions with virus-specific RNA ligands.
Damien Arnoult - One of the best experts on this subject based on the ideXlab platform.
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The role of optineurin in antiviral type I interferon production
Frontiers in Immunology, 2018Co-Authors: Ahmed Outlioua, Marie Pourcelot, Damien ArnoultAbstract:After a viral infection and the stimulation of some pattern-recognition Receptors as the toll-like receptor 3 in the endosomes or the RIG-I-like Receptors in the cytosol, activation of the IKK-related kinase TBK1 leads to the production of type I interferons (IFNs) after phosphorylation of the transcription factors IRF3 and IRF7. Recent findings indicate an involvement of K63-linked polyubiquitination and of the Golgi-localized protein optineurin (OPTN) in the activation of this crucial kinase involved in innate antiviral immunity. This review summarizes the sensing of viruses and the signaling leading to type I IFN production following TBK1 activation through its ubiquitination and the sensing of ubiquitin chains by OPTN at the Golgi apparatus.
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Mitochondrial anti-viral immunity.
The international journal of biochemistry & cell biology, 2012Co-Authors: Naima Zemirli, Damien ArnoultAbstract:In the cytosol, the sensing of RNA viruses by the RIG-I-like Receptors (RLRs) triggers a complex signaling cascade where the mitochondrial antiviral signaling protein (MAVS) plays a crucial role in orchestrating the innate host response through the induction of antiviral and inflammatory responses. Hence, in addition to their known roles in the metabolic processes and the control of programmed cell death, mitochondria are now emerging as a fundamental hub for innate anti-viral immunity. This review summarizes the findings related to the MAVS adapter and mitochondria in the innate immune response to RNA viruses.
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MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like Receptors
BMC Biology, 2012Co-Authors: Céline Castanier, Naima Zemirli, Nicolas Bidère, Alain Portier, Aimé Vazquez, Dominique Garcin, Damien ArnoultAbstract:Background During a viral infection, the intracellular RIG-I-like Receptors (RLRs) sense viral RNA and signal through the mitochondrial antiviral signaling adaptor MAVS (also known as IPS-1, Cardif and VISA) whose activation triggers a rapid production of type I interferons (IFN) and of pro-inflammatory cytokines through the transcription factors IRF3/IRF7 and NF-κB, respectively. While MAVS is essential for this signaling and known to operate through the scaffold protein NEMO and the protein kinase TBK1 that phosphorylates IRF3, its mechanism of action and regulation remain unclear.
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MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I Interferon production after activation of the antiviral RIG-I-like Receptors.
BMC Biology, 2012Co-Authors: Céline Castanier, Naima Zemirli, Nicolas Bidère, Alain Portier, Aimé Vazquez, Dominique Garcin, Damien ArnoultAbstract:ABSTRACT: BACKGROUND: During a viral infection, the intracellular RIG-I-like Receptors (RLRs) sense viral RNA and signal through the mitochondrial antiviral signaling adaptor MAVS (also known as IPS-1, Cardif and VISA) whose activation triggers a rapid production of type I interferons (IFN) and of pro-inflammatory cytokines through the transcription factors IRF3/IRF7 and NF-kappaB, respectively. While MAVS is essential for this signaling and known to operate through the scaffold protein NEMO and the protein kinase TBK1 that phosphorylates IRF3, its mechanism of action and regulation remain unclear. RESULTS: We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. Inhibition of this MAVS degradation with a proteasome inhibitor does not affect NF-kappaB signaling but it hampers IRF3 activation, and NEMO and TBK1, two essential mediators in type I IFN production, are retained at the mitochondria. CONCLUSIONS: These results suggest that MAVS functions as a recruitment platform that assembles a signaling complex involving NEMO and TBK1, and that the proteasome-mediated MAVS degradation is required to release the signaling complex into the cytosol, allowing IRF3 phosphorylation by TBK1.
