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Takao Fujii - One of the best experts on this subject based on the ideXlab platform.
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the rig i like Receptor ifih1 mda5 is a dermatomyositis specific autoantigen identified by the anti cadm 140 antibody
Rheumatology, 2010Co-Authors: Ran Nakashima, Yoshitaka Imura, Shio Kobayashi, Naoichiro Yukawa, Hajime Yoshifuji, Takaki Nojima, Daisuke Kawabata, Koichiro Ohmura, Takashi Usui, Takao FujiiAbstract:Objectives. Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. Methods. Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [ 35 S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. Results. The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like Receptors and plays a role in innate immune responses. Conclusion. The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.
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The RIG-I-like Receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody
Rheumatology, 2009Co-Authors: Ran Nakashima, Yoshitaka Imura, Shio Kobayashi, Naoichiro Yukawa, Hajime Yoshifuji, Takaki Nojima, Daisuke Kawabata, Koichiro Ohmura, Takashi Usui, Takao FujiiAbstract:Objectives. Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. Methods. Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [ 35 S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. Results. The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like Receptors and plays a role in innate immune responses. Conclusion. The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.
Ran Nakashima - One of the best experts on this subject based on the ideXlab platform.
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the rig i like Receptor ifih1 mda5 is a dermatomyositis specific autoantigen identified by the anti cadm 140 antibody
Rheumatology, 2010Co-Authors: Ran Nakashima, Yoshitaka Imura, Shio Kobayashi, Naoichiro Yukawa, Hajime Yoshifuji, Takaki Nojima, Daisuke Kawabata, Koichiro Ohmura, Takashi Usui, Takao FujiiAbstract:Objectives. Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. Methods. Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [ 35 S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. Results. The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like Receptors and plays a role in innate immune responses. Conclusion. The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.
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The RIG-I-like Receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody
Rheumatology, 2009Co-Authors: Ran Nakashima, Yoshitaka Imura, Shio Kobayashi, Naoichiro Yukawa, Hajime Yoshifuji, Takaki Nojima, Daisuke Kawabata, Koichiro Ohmura, Takashi Usui, Takao FujiiAbstract:Objectives. Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. Methods. Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [ 35 S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. Results. The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like Receptors and plays a role in innate immune responses. Conclusion. The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.
Curt M. Horvath - One of the best experts on this subject based on the ideXlab platform.
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lgp2 synergy with mda5 in rlr mediated rna recognition and antiviral signaling
Cytokine, 2015Co-Authors: Annie M. Bruns, Curt M. HorvathAbstract:Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral response. Pattern recognition Receptor proteins detect molecular signatures of virus infection and activate antiviral signaling. The RIG-I-like Receptor (RLR) proteins are expressed in the cytoplasm of nearly all cells and specifically recognize virus-derived RNA species as a molecular feature discriminating the pathogen from the host. The RLR family is composed of three homologous proteins, RIG-I, MDA5, and LGP2. All RLRs have the ability to detect virus-derived dsRNA and hydrolyze ATP, but display individual differences in enzymatic activity, intrinsic ability to recognize RNA, and mechanisms of activation. Emerging evidence suggests that MDA5 and RIG-I utilize distinct mechanisms to form oligomeric complexes along dsRNA. Aligning of their signaling domains creates a platform capable of propagating and amplifying antiviral signaling responses. LGP2 with intact ATP hydrolysis is critical for the MDA5-mediated antiviral response, but LGP2 lacks the domains essential for activation of antiviral signaling, leaving the role of LGP2 in antiviral signaling unclear. Recent studies revealed a mechanistic basis of synergy between LGP2 and MDA5 leading to enhanced antiviral signaling. This review briefly summarizes the RLR system, and focuses on the relationship between LGP2 and MDA5, describing in detail how these two proteins work together to detect foreign RNA and generate a fully functional antiviral response.
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mda5 and lgp2 accomplices and antagonists of antiviral signal transduction
Journal of Virology, 2014Co-Authors: Kenny R Rodriguez, Annie M. Bruns, Curt M. HorvathAbstract:ABSTRACT Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral transcriptional response that provides an initial barrier to replication and impacts both innate and adaptive immune responses. Retinoic acid-inducible gene I (RIG-I)-like Receptor (RLR) proteins mediate intracellular virus recognition and are activated by viral RNA ligands to induce antiviral signal transduction. While the mechanisms of RIG-I regulation are already well understood, less is known about the more enigmatic melanoma differentiation-associated 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2). Emerging evidence suggests that these two RLRs are intimately associated as both accomplices and antagonists of antiviral signal transduction.
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P143 Single molecule analysis of the RIG-I-like Receptor, LGP2
Cytokine, 2012Co-Authors: Annie M. Bruns, Darja Pollpeter, Nastaran Hadizadeh, Sua Myong, John F. Marko, Curt M. HorvathAbstract:Introduction The RIG-I-like Receptor (RLR) proteins, RIG-I, MDA5, and LGP2 are cytoplasmic DExD/H box proteins that function to specifically recognize molecular features of RNA species that discriminate the pathogen from the host. Both RIG-I and MDA5 are able to activate downstream antiviral signal transduction, while LGP2 has been linked to diverse effector functions both upstream and downstream of RIG-I and MDA5, leaving the overall function of LGP2 largely unresolved. All of the RLRs bind dsRNA with varying affinities and exhibit RNA-enhanced ATP hydrolysis activity. The RNA binding ability of these proteins is critical for antiviral responses, but the importance of ATP hydrolysis is poorly understood. Methods We have utilized biochemical methods and single molecule TIRF microscopy-based imaging to investigate the enzymatic and RNA binding activities of LGP2 and mutant variants. Results LGP2 was found to have a uniquely high level of basal ATP hydrolysis activity in the absence of dsRNA, in addition to the dsRNA-enhanced ATP hydrolysis activity. These two enzymatic activities are separable by specific point mutations to LGP2 that create defects in basal, but not dsRNA-stimulated, ATP hydrolysis. Single molecule analysis of LGP2-dsRNA interaction revealed no evidence for ATP-driven LGP2 translocation on dsRNA, as was reported for RIG-I. Instead, we observe that ATP hydrolysis activity enhances the ability of LGP2 to engage dsRNA. This ATP-enhancement of dsRNA binding requires basal ATP hydrolysis activity, and enables LGP2 to form more interactions with diverse dsRNA ligands that are intrinsically poor substrates. Conclusion These findings indicate LGP2 uses basal ATP hydrolysis to enable recognition of a broader range of target dsRNA ligands.
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Activation of RIG-I-like Receptor signal transduction
Critical Reviews in Biochemistry and Molecular Biology, 2011Co-Authors: Annie M. Bruns, Curt M. HorvathAbstract:Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral response. Pattern recognition Receptor proteins detect molecular signatures of virus infection and activate antiviral signaling cascades. The RIG-I-like Receptors are cytoplasmic DExD/H box proteins that can specifically recognize virus-derived RNA species as a molecular feature discriminating the pathogen from the host. The RIG-I-like Receptor family is composed of three homologous proteins, RIG-I, MDA5, and LGP2. All of these proteins can bind double-stranded RNA species with varying affinities via their conserved DExD/H box RNA helicase domains and C-terminal regulatory domains. The recognition of foreign RNA by the RLRs activates enzymatic functions and initiates signal transduction pathways resulting in the production of antiviral cytokines and the establishment of a broadly effective cellular antiviral state that protects neighboring cells from infection and triggers innate and adaptive immune systems. The p...
Takashi Fujita - One of the best experts on this subject based on the ideXlab platform.
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A Novel Function of Human Pumilio Proteins in Cytoplasmic Sensing of Viral Infection
PLoS Pathogens, 2014Co-Authors: Ryo Narita, Etsu Murakami, Emi Hirano, Seiji P. Yamamoto, Kiyohiro Takahasi, Hiroki Kato, Mitsutoshi Yoneyama, Takashi FujitaAbstract:RIG-I-like Receptor (RLR) plays a pivotal role in the detection of invading pathogens to initiate type I interferon (IFN) gene transcription. Since aberrant IFN production is harmful, RLR signaling is strictly regulated. However, the regulatory mechanisms are not fully understood. By expression cloning, we identified Pumilio proteins, PUM1 and PUM2, as candidate positive regulators of RIG-I signaling. Overexpression of Pumilio proteins and their knockdown augmented and diminished IFN-β promoter activity induced by Newcastle disease virus (NDV), respectively. Both proteins showed a specific association with LGP2, but not with RIG-I or MDA5. Furthermore, all of these components were recruited to NDV-induced antiviral stress granules. Interestingly, biochemical analyses revealed that Pumilio increased double-stranded (ds) RNA binding affinity of LGP2; however, Pumilio was absent in the dsRNA-LGP2 complex, suggesting that Pumilio facilitates viral RNA recognition by LGP2 through its chaperon-like function. Collectively, our results demonstrate an unknown function of Pumilio in viral recognition by LGP2.
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Type I Interferon Production Induced by RIG-I-like Receptors
Journal of Interferon and Cytokine Research, 2010Co-Authors: Koji Onomoto, Kiyohiro Takahasi, Kazuhide Onoguchi, Takashi FujitaAbstract:Type I interferon (IFN) is produced in a variety of tissues in the body in response to viral infections. Recent studies have revealed that cytoplasmic Receptors for viral (nonself) RNA are responsible for triggering IFN production. Different viruses activate different sensors. Numerous signaling adaptors are reported to participate in the regulation of the IFN gene's activation. In this paper, the role of free polyubiquitine chains in the activation of retinoic acid inducible gene I (RIG-I)-like Receptors and the involvement of mitochondria as a signaling platform in the modulation of RIG-I-like Receptor signaling is reviewed.
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solution structures of cytosolic rna sensor mda5 and lgp2 c terminal domains identification of the rna recognition loop in rig i like Receptors
Journal of Biological Chemistry, 2009Co-Authors: Kiyohiro Takahasi, Ryo Narita, Mitsutoshi Yoneyama, Taeko Shigemoto, Reiko Hirai, Hiroyuki Kumeta, Natsuko Tsuduki, Masataka Horiuchi, Kenji Ogura, Takashi FujitaAbstract:Abstract The RIG-I like Receptor (RLR) comprises three homologues: RIG-I (retinoic acid-inducible gene I), MDA5 (melanoma differentiation-associated gene 5), and LGP2 (laboratory of genetics and physiology 2). Each RLR senses different viral infections by recognizing replicating viral RNA in the cytoplasm. The RLR contains a conserved C-terminal domain (CTD), which is responsible for the binding specificity to the viral RNAs, including double-stranded RNA (dsRNA) and 5′-triphosphated single-stranded RNA (5′ppp-ssRNA). Here, the solution structures of the MDA5 and LGP2 CTD domains were solved by NMR and compared with those of RIG-I CTD. The CTD domains each have a similar fold and a similar basic surface but there is the distinct structural feature of a RNA binding loop; The LGP2 and RIG-I CTD domains have a large basic surface, one bank of which is formed by the RNA binding loop. MDA5 also has a large basic surface that is extensively flat due to open conformation of the RNA binding loop. The NMR chemical shift perturbation study showed that dsRNA and 5′ppp-ssRNA are bound to the basic surface of LGP2 CTD, whereas dsRNA is bound to the basic surface of MDA5 CTD but much more weakly, indicating that the conformation of the RNA binding loop is responsible for the sensitivity to dsRNA and 5′ppp-ssRNA. Mutation study of the basic surface and the RNA binding loop supports the conclusion from the structure studies. Thus, the CTD is responsible for the binding affinity to the viral RNAs.
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identification of loss of function mutations in human genes encoding rig i and mda5 implications for resistance to type i diabetes
Journal of Biological Chemistry, 2009Co-Authors: Taeko Shigemoto, Mitsutoshi Yoneyama, Maiko Kageyama, Reiko Hirai, Jiping Zheng, Takashi FujitaAbstract:Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are essential for detecting viral RNA and triggering antiviral responses, including production of type I interferon. We analyzed the phenotype of non-synonymous mutants of human RIG-I and MDA5 reported in databases by functional complementation in cell cultures. Of seven missense mutations of RIG-I, S183I, which occurs within the second caspase recruitment domain repeat, inactivated this domain and conferred a dominant inhibitory function. Of 10 mutants of MDA5, two exhibited loss of function. A nonsense mutation, E627*, resulted in deletion of the C-terminal region and double-stranded RNA (dsRNA) binding activity. Another loss of function mutation, I923V, which occurs within the C-terminal domain, did not affect dsRNA binding activity, suggesting a novel and essential role for this residue in the signaling. Remarkably, these mutations are implicated in resistance to type I diabetes. However, the A946T mutation of MDA5, which has been implicated in type I diabetes by previous genetic analyses, affected neither dsRNA binding nor IFN gene activation. These results provide new insights into the structure-function relationship of RIG-I-like Receptors as well as into human RIG-I-like Receptor polymorphisms, antiviral innate immunity, and autoimmune diseases.
Yoshitaka Imura - One of the best experts on this subject based on the ideXlab platform.
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the rig i like Receptor ifih1 mda5 is a dermatomyositis specific autoantigen identified by the anti cadm 140 antibody
Rheumatology, 2010Co-Authors: Ran Nakashima, Yoshitaka Imura, Shio Kobayashi, Naoichiro Yukawa, Hajime Yoshifuji, Takaki Nojima, Daisuke Kawabata, Koichiro Ohmura, Takashi Usui, Takao FujiiAbstract:Objectives. Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. Methods. Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [ 35 S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. Results. The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like Receptors and plays a role in innate immune responses. Conclusion. The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.
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The RIG-I-like Receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody
Rheumatology, 2009Co-Authors: Ran Nakashima, Yoshitaka Imura, Shio Kobayashi, Naoichiro Yukawa, Hajime Yoshifuji, Takaki Nojima, Daisuke Kawabata, Koichiro Ohmura, Takashi Usui, Takao FujiiAbstract:Objectives. Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. Methods. Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [ 35 S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. Results. The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like Receptors and plays a role in innate immune responses. Conclusion. The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.
