{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/1026"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/1026","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Mechanism of Ubiquitin Induced Activation of RIG-I Like Receptors in Antiviral Innate Immunity","abstract":"The innate immune response is the first line of defense against viral infections. Innate immune recognition is mediated by a set of host pattern recognition receptors that can recognize pathogen associated molecular patterns, and trigger the expression of immune response genes. Two proteins of the RIG-I like receptor family, RIG-I and MDA5, are essential for the detection of viral RNA in the cytoplasm. Upon viral recognition, RIG-I and MDA5 activate the mitochondrial signaling protein AVS, and initiate downstream signaling pathways that activate the transcription factors NF-kappaB and IRF3. These transcription factors regulate the production of type I interferons and proinflammatory cytokines, which serve to keep virus infections under control. RIG-I and MDA5 contain N-terminal tandem CARD domains. CARD domains in other proteins are known to mediate protein-protein interactions. MAVS also contain one CARD domain. It has been proposed that the activation of MAVS by RIG-I is mediated by homotypic interaction between their CARD domains. However, it is hard to detect stable interaction between the CARD domains of RIG-I and that of MAVS. Therefore, the underlying biochemical mechanisms of how activation signals are transduced from a cytosolic receptor, RIG-I, to a mitochondria signaling protein, MAVS, is not clear. Protein ubiquitination have pivotal roles in diverse cell signaling pathways, including those in the immune system. A ubiquitin E3 ligase, TRIM25, promotes Lysine 63-linked polyubiquitination of RIG-I, and is essential for the RIG-I antiviral pathway. However, the biochemical mechanisms by which RIG-I is activated by ubiquitin remain poorly understood. In addition, whether ubiquitination is involved in MDA5 activation is unknown. Here, I describe the development of an in vitro biochemical assay to detect MAVS activation by a cytosolic activator. Purification of this activator revealed an important role of ubiquitin in RIG-I activation. Biochemical characterization of the ubiquitin induced RIG-I activation process revealed a new mechanism by which ubiquitin regulates cell signaling that involves the formation of a polyubiquitin-induced tetrameric complex. In addition, polyubiquitin-induced oligomerization appears to be a conserved mechanism for both MDA5 and RIG-I activation.","abstract_html":"The innate immune response is the first line of defense against viral infections. Innate immune recognition is mediated by a set of host pattern recognition receptors that can recognize pathogen associated molecular patterns, and trigger the expression of immune response genes. Two proteins of the RIG-I like receptor family, RIG-I and MDA5, are essential for the detection of viral RNA in the cytoplasm. Upon viral recognition, RIG-I and MDA5 activate the mitochondrial signaling protein AVS, and initiate downstream signaling pathways that activate the transcription factors NF-kappaB and IRF3. These transcription factors regulate the production of type I interferons and proinflammatory cytokines, which serve to keep virus infections under control. RIG-I and MDA5 contain N-terminal tandem CARD domains. CARD domains in other proteins are known to mediate protein-protein interactions. MAVS also contain one CARD domain. It has been proposed that the activation of MAVS by RIG-I is mediated by homotypic interaction between their CARD domains. However, it is hard to detect stable interaction between the CARD domains of RIG-I and that of MAVS. Therefore, the underlying biochemical mechanisms of how activation signals are transduced from a cytosolic receptor, RIG-I, to a mitochondria signaling protein, MAVS, is not clear. Protein ubiquitination have pivotal roles in diverse cell signaling pathways, including those in the immune system. A ubiquitin E3 ligase, TRIM25, promotes Lysine 63-linked polyubiquitination of RIG-I, and is essential for the RIG-I antiviral pathway. However, the biochemical mechanisms by which RIG-I is activated by ubiquitin remain poorly understood. In addition, whether ubiquitination is involved in MDA5 activation is unknown. Here, I describe the development of an in vitro biochemical assay to detect MAVS activation by a cytosolic activator. Purification of this activator revealed an important role of ubiquitin in RIG-I activation. Biochemical characterization of the ubiquitin induced RIG-I activation process revealed a new mechanism by which ubiquitin regulates cell signaling that involves the formation of a polyubiquitin-induced tetrameric complex. In addition, polyubiquitin-induced oligomerization appears to be a conserved mechanism for both MDA5 and RIG-I activation.","abstract_has_math":false,"creators":["Jiang, Xiaomo"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Chen, Zhijian J."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012-07-20T19:18:50Z","date_published":"2012-07-20T19:18:50Z","updated_at":"2026-07-24T05:52:11Z","subjects":["Polyubiquitin","DEAD-box RNA Helicases","Encephalomyocarditis virus"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["810335906"],"render_values":[{"text":"810335906","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/1026","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Chen, Zhijian J."]},{"key":"dc:creator","label":"Author","values":["Jiang, Xiaomo"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2012-07-20T19:18:50Z","2012-07-20"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Polyubiquitin","DEAD-box RNA Helicases","Encephalomyocarditis virus"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/1026","810335906"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The innate immune response is the first line of defense against viral infections. Innate immune recognition is mediated by a set of host pattern recognition receptors that can recognize pathogen associated molecular patterns, and trigger the expression of immune response genes. Two proteins of the RIG-I like receptor family, RIG-I and MDA5, are essential for the detection of viral RNA in the cytoplasm. Upon viral recognition, RIG-I and MDA5 activate the mitochondrial signaling protein AVS, and initiate downstream signaling pathways that activate the transcription factors NF-kappaB and IRF3. These transcription factors regulate the production of type I interferons and proinflammatory cytokines, which serve to keep virus infections under control. RIG-I and MDA5 contain N-terminal tandem CARD domains. CARD domains in other proteins are known to mediate protein-protein interactions. MAVS also contain one CARD domain. It has been proposed that the activation of MAVS by RIG-I is mediated by homotypic interaction between their CARD domains. However, it is hard to detect stable interaction between the CARD domains of RIG-I and that of MAVS. Therefore, the underlying biochemical mechanisms of how activation signals are transduced from a cytosolic receptor, RIG-I, to a mitochondria signaling protein, MAVS, is not clear. Protein ubiquitination have pivotal roles in diverse cell signaling pathways, including those in the immune system. A ubiquitin E3 ligase, TRIM25, promotes Lysine 63-linked polyubiquitination of RIG-I, and is essential for the RIG-I antiviral pathway. However, the biochemical mechanisms by which RIG-I is activated by ubiquitin remain poorly understood. In addition, whether ubiquitination is involved in MDA5 activation is unknown. Here, I describe the development of an in vitro biochemical assay to detect MAVS activation by a cytosolic activator. Purification of this activator revealed an important role of ubiquitin in RIG-I activation. Biochemical characterization of the ubiquitin induced RIG-I activation process revealed a new mechanism by which ubiquitin regulates cell signaling that involves the formation of a polyubiquitin-induced tetrameric complex. In addition, polyubiquitin-induced oligomerization appears to be a conserved mechanism for both MDA5 and RIG-I activation."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Mechanism of Ubiquitin Induced Activation of RIG-I Like Receptors in Antiviral Innate Immunity"]}]}],"canonical_facts":{"dc:contributor":["Chen, Zhijian J."],"dc:creator":["Jiang, Xiaomo"],"dc:date":["2012-07-20T19:18:50Z","2012-07-20"],"dc:description":["The innate immune response is the first line of defense against viral infections. Innate immune recognition is mediated by a set of host pattern recognition receptors that can recognize pathogen associated molecular patterns, and trigger the expression of immune response genes. Two proteins of the RIG-I like receptor family, RIG-I and MDA5, are essential for the detection of viral RNA in the cytoplasm. Upon viral recognition, RIG-I and MDA5 activate the mitochondrial signaling protein AVS, and initiate downstream signaling pathways that activate the transcription factors NF-kappaB and IRF3. These transcription factors regulate the production of type I interferons and proinflammatory cytokines, which serve to keep virus infections under control. RIG-I and MDA5 contain N-terminal tandem CARD domains. CARD domains in other proteins are known to mediate protein-protein interactions. MAVS also contain one CARD domain. It has been proposed that the activation of MAVS by RIG-I is mediated by homotypic interaction between their CARD domains. However, it is hard to detect stable interaction between the CARD domains of RIG-I and that of MAVS. Therefore, the underlying biochemical mechanisms of how activation signals are transduced from a cytosolic receptor, RIG-I, to a mitochondria signaling protein, MAVS, is not clear. Protein ubiquitination have pivotal roles in diverse cell signaling pathways, including those in the immune system. A ubiquitin E3 ligase, TRIM25, promotes Lysine 63-linked polyubiquitination of RIG-I, and is essential for the RIG-I antiviral pathway. However, the biochemical mechanisms by which RIG-I is activated by ubiquitin remain poorly understood. In addition, whether ubiquitination is involved in MDA5 activation is unknown. Here, I describe the development of an in vitro biochemical assay to detect MAVS activation by a cytosolic activator. Purification of this activator revealed an important role of ubiquitin in RIG-I activation. Biochemical characterization of the ubiquitin induced RIG-I activation process revealed a new mechanism by which ubiquitin regulates cell signaling that involves the formation of a polyubiquitin-induced tetrameric complex. In addition, polyubiquitin-induced oligomerization appears to be a conserved mechanism for both MDA5 and RIG-I activation."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/1026","810335906"],"dc:language":["en"],"dc:subject":["Polyubiquitin","DEAD-box RNA Helicases","Encephalomyocarditis virus"],"dc:title":["Mechanism of Ubiquitin Induced Activation of RIG-I Like Receptors in Antiviral Innate Immunity"],"dc:type":["Thesis","Text"]},"updated_at":"2026-07-24T05:52:11Z"}