The Experts below are selected from a list of 1713 Experts worldwide ranked by ideXlab platform
Zhijian J Chen - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial antiviral signaling Protein mavs monitors commensal bacteria and induces an immune response that prevents experimental colitis
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Xiao Dong Li, Yu Hsin Chiu, Anisa S Ismail, Cassie L Behrendt, Mary Wightcarter, Lora V Hooper, Zhijian J ChenAbstract:RIG-I–like receptors (RLRs) activate host innate immune responses against virus infection through recruiting the Mitochondrial adaptor Protein MAVS (also known as IPS1, VISA, or CARDIF). Here we show that MAVS also plays a pivotal role in maintaining intestinal homeostasis. We found that MAVS knockout mice developed more severe mortality and morbidity than WT animals in an experimental model of colitis. Bone marrow transplantation experiments revealed that MAVS in cells of nonhematopoietic origin plays a dominant role in the protection against colitis. Importantly, RNA species derived from intestinal commensal bacteria activate the RIG-I–MAVS pathway to induce the production of multiple cytokines and antimicrobial peptides, including IFN-β and RegIIIγ. These results unveil a previously unexplored role of MAVS in monitoring intestinal commensal bacteria and maintaining tissue homeostasis.
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Key Role of Ubc5 and Lysine-63 Polyubiquitination in Viral Activation of IRF3
Molecular cell, 2009Co-Authors: Wenwen Zeng, Lijun Sun, Siqi Liu, Zhijian J ChenAbstract:The Mitochondrial antiviral signaling Protein (MAVS; also known as IPS-1, VISA, and CARDIF) is essential for innate immune response against RNA viruses. MAVS transduces signals from the cytosolic RIG-I-like receptors, which bind to viral RNAs. But how MAVS activates downstream transcription factors such as IRF3 to induce type-I interferons is not well understood. We have established a cell-free system in which mitochondria derived from virus-infected cells activate IRF3 in the cytosol. Fractionation of the cytosol led to the identification of Ubc5 as a ubiquitin-conjugating enzyme (E2) required for IRF3 activation. Using an inducible RNAi strategy, we demonstrate that catalytically active Ubc5 is required for IRF3 activation by viral infection. The activation of IRF3 also requires two ubiquitin-binding domains of NEMO. Furthermore, we show that replacement of endogenous ubiquitin with its K63R mutant abolishes viral activation of IRF3, demonstrating that K63 polyubiquitination plays a key role in IRF3 activation.
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The Specific and Essential Role of MAVS in Antiviral Innate Immune Responses
Immunity, 2006Co-Authors: Qinmiao Sun, Rashu B Seth, Lijun Sun, Hong Hsing Liu, Xiang Chen, James Forman, Zhijian J ChenAbstract:The Mitochondrial antiviral signaling Protein (MAVS) mediates the activation of NFκB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by cytosolic DNA, but the in vivo evidence is lacking. By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFκB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs). However, MAVS was not required for interferon induction by cytosolic DNA or by Listeria monocytogenes. Mice lacking MAVS were viable and fertile, but they failed to induce interferons in response to poly(I:C) stimulation and were severely compromised in immune defense against viral infection. These results provide the in vivo evidence that the cytosolic viral signaling pathway through MAVS is specifically required for innate immune responses against viral infection.
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Hepatitis C virus protease NS3/4A cleaves Mitochondrial antiviral signaling Protein off the mitochondria to evade innate immunity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Lijun Sun, Gabriel Pineda, Rashu B Seth, Zhijian J ChenAbstract:Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the Mitochondrial antiviral signaling Protein, MAVS, that activates NF-κB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the Mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host–pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral Protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
Ting Ye - One of the best experts on this subject based on the ideXlab platform.
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tachypleus tridentatus lectin enhances oncolytic vaccinia virus replication to suppress in vivo hepatocellular carcinoma growth
Marine Drugs, 2018Co-Authors: Gongchu Li, Jianhong Cheng, Tao Wu, Ting YeAbstract:Lectins play diverse roles in physiological processes as biological recognition molecules. In this report, a gene encoding Tachypleus tridentatus Lectin (TTL) was inserted into an oncolytic vaccinia virus (oncoVV) vector to form oncoVV-TTL, which showed significant antitumor activity in a hepatocellular carcinoma mouse model. Furthermore, TTL enhanced oncoVV replication through suppressing antiviral factors expression such as interferon-inducible Protein 16 (IFI16), Mitochondrial antiviral signaling Protein (MAVS) and interferon-beta (IFN-β). Further investigations revealed that oncoVV-TTL replication was highly dependent on ERK activity. This study might provide insights into a novel way of the utilization of TTL in oncolytic viral therapies.
Rashu B Seth - One of the best experts on this subject based on the ideXlab platform.
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The Specific and Essential Role of MAVS in Antiviral Innate Immune Responses
Immunity, 2006Co-Authors: Qinmiao Sun, Rashu B Seth, Lijun Sun, Hong Hsing Liu, Xiang Chen, James Forman, Zhijian J ChenAbstract:The Mitochondrial antiviral signaling Protein (MAVS) mediates the activation of NFκB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by cytosolic DNA, but the in vivo evidence is lacking. By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFκB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs). However, MAVS was not required for interferon induction by cytosolic DNA or by Listeria monocytogenes. Mice lacking MAVS were viable and fertile, but they failed to induce interferons in response to poly(I:C) stimulation and were severely compromised in immune defense against viral infection. These results provide the in vivo evidence that the cytosolic viral signaling pathway through MAVS is specifically required for innate immune responses against viral infection.
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hepatitis c virus protease ns3 4a cleaves Mitochondrial antiviral signaling Protein off the mitochondria to evade innate immunity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Xiao Dong Li, Rashu B Seth, Gabriel PinedaAbstract:Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the Mitochondrial antiviral signaling Protein, MAVS, that activates NF-κB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the Mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host–pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral Protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
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Hepatitis C virus protease NS3/4A cleaves Mitochondrial antiviral signaling Protein off the mitochondria to evade innate immunity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Lijun Sun, Gabriel Pineda, Rashu B Seth, Zhijian J ChenAbstract:Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the Mitochondrial antiviral signaling Protein, MAVS, that activates NF-κB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the Mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host–pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral Protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
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identification and characterization of mavs a Mitochondrial antiviral signaling Protein that activates nf κb and irf3
Cell, 2005Co-Authors: Rashu B Seth, Lijun SunAbstract:Viral infection triggers host innate immune responses through activation of the transcription factors NF-kappaB and IRF 3, which coordinately regulate the expression of type-I interferons such as interferon-beta (IFN-beta). Herein, we report the identification of a novel Protein termed MAVS (Mitochondrial antiviral signaling), which mediates the activation of NF-kappaB and IRF 3 in response to viral infection. Silencing of MAVS expression through RNA interference abolishes the activation of NF-kappaB and IRF 3 by viruses, thereby permitting viral replication. Conversely, overexpression of MAVS induces the expression of IFN-beta through activation of NF-kappaB and IRF 3, thus boosting antiviral immunity. Epistasis experiments show that MAVS is required for the phosphorylation of IRF 3 and IkappaB and functions downstream of RIG-I, an intracellular receptor for viral RNA. MAVS contains an N-terminal CARD-like domain and a C-terminal transmembrane domain, both of which are essential for MAVS signaling. The transmembrane domain targets MAVS to the mitochondria, implicating a new role of mitochondria in innate immunity.
Lijun Sun - One of the best experts on this subject based on the ideXlab platform.
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Key Role of Ubc5 and Lysine-63 Polyubiquitination in Viral Activation of IRF3
Molecular cell, 2009Co-Authors: Wenwen Zeng, Lijun Sun, Siqi Liu, Zhijian J ChenAbstract:The Mitochondrial antiviral signaling Protein (MAVS; also known as IPS-1, VISA, and CARDIF) is essential for innate immune response against RNA viruses. MAVS transduces signals from the cytosolic RIG-I-like receptors, which bind to viral RNAs. But how MAVS activates downstream transcription factors such as IRF3 to induce type-I interferons is not well understood. We have established a cell-free system in which mitochondria derived from virus-infected cells activate IRF3 in the cytosol. Fractionation of the cytosol led to the identification of Ubc5 as a ubiquitin-conjugating enzyme (E2) required for IRF3 activation. Using an inducible RNAi strategy, we demonstrate that catalytically active Ubc5 is required for IRF3 activation by viral infection. The activation of IRF3 also requires two ubiquitin-binding domains of NEMO. Furthermore, we show that replacement of endogenous ubiquitin with its K63R mutant abolishes viral activation of IRF3, demonstrating that K63 polyubiquitination plays a key role in IRF3 activation.
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The Specific and Essential Role of MAVS in Antiviral Innate Immune Responses
Immunity, 2006Co-Authors: Qinmiao Sun, Rashu B Seth, Lijun Sun, Hong Hsing Liu, Xiang Chen, James Forman, Zhijian J ChenAbstract:The Mitochondrial antiviral signaling Protein (MAVS) mediates the activation of NFκB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by cytosolic DNA, but the in vivo evidence is lacking. By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFκB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs). However, MAVS was not required for interferon induction by cytosolic DNA or by Listeria monocytogenes. Mice lacking MAVS were viable and fertile, but they failed to induce interferons in response to poly(I:C) stimulation and were severely compromised in immune defense against viral infection. These results provide the in vivo evidence that the cytosolic viral signaling pathway through MAVS is specifically required for innate immune responses against viral infection.
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Hepatitis C virus protease NS3/4A cleaves Mitochondrial antiviral signaling Protein off the mitochondria to evade innate immunity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Lijun Sun, Gabriel Pineda, Rashu B Seth, Zhijian J ChenAbstract:Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the Mitochondrial antiviral signaling Protein, MAVS, that activates NF-κB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the Mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host–pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral Protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
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identification and characterization of mavs a Mitochondrial antiviral signaling Protein that activates nf κb and irf3
Cell, 2005Co-Authors: Rashu B Seth, Lijun SunAbstract:Viral infection triggers host innate immune responses through activation of the transcription factors NF-kappaB and IRF 3, which coordinately regulate the expression of type-I interferons such as interferon-beta (IFN-beta). Herein, we report the identification of a novel Protein termed MAVS (Mitochondrial antiviral signaling), which mediates the activation of NF-kappaB and IRF 3 in response to viral infection. Silencing of MAVS expression through RNA interference abolishes the activation of NF-kappaB and IRF 3 by viruses, thereby permitting viral replication. Conversely, overexpression of MAVS induces the expression of IFN-beta through activation of NF-kappaB and IRF 3, thus boosting antiviral immunity. Epistasis experiments show that MAVS is required for the phosphorylation of IRF 3 and IkappaB and functions downstream of RIG-I, an intracellular receptor for viral RNA. MAVS contains an N-terminal CARD-like domain and a C-terminal transmembrane domain, both of which are essential for MAVS signaling. The transmembrane domain targets MAVS to the mitochondria, implicating a new role of mitochondria in innate immunity.
Gabriel Pineda - One of the best experts on this subject based on the ideXlab platform.
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hepatitis c virus protease ns3 4a cleaves Mitochondrial antiviral signaling Protein off the mitochondria to evade innate immunity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Xiao Dong Li, Rashu B Seth, Gabriel PinedaAbstract:Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the Mitochondrial antiviral signaling Protein, MAVS, that activates NF-κB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the Mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host–pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral Protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
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Hepatitis C virus protease NS3/4A cleaves Mitochondrial antiviral signaling Protein off the mitochondria to evade innate immunity
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Lijun Sun, Gabriel Pineda, Rashu B Seth, Zhijian J ChenAbstract:Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the Mitochondrial antiviral signaling Protein, MAVS, that activates NF-κB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the Mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host–pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral Protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.