Key Roles of Ubiquitination and Phosphorylation in RIG-I/MAVS Viral Sensing Pathway

dc.contributor.advisorOlson, Eric N.en
dc.contributor.committeeMembervan Oers, Nicolai S. C.en
dc.contributor.committeeMemberDe Martino, Georgeen
dc.creatorLiu, Siqi 1983-en
dc.date.accessioned2015-06-01T18:53:58Z
dc.date.available2015-06-01T18:53:58Z
dc.date.created2013-05
dc.date.issued2013-04-17
dc.date.submittedMay 2013
dc.date.updated2015-06-01T18:53:28Z
dc.description.abstractRNA virus infections are detected by the RIG-I family of receptors, which induce the production of type-I interferons (IFNs) and other antiviral molecules through the mitochondrial membrane protein MAVS. We have recently shown that MAVS forms large prion-like aggregates in response to virus infection and that these aggregates are highly potent in activating the cytosolic kinases IKK and TBK1, which in turn activate NF-κB and IRF3, respectively, to induce IFNs. However, the mechanisms remain unknown. Here I showed that MAVS aggregates recruited several TRAF proteins, including TRAF2, TRAF3, TRAF5 and TRAF6, through two distinct TRAF binding motifs. Mutations of both motifs in MAVS that disrupted its binding to the TRAF proteins were necessary to abrogate its ability to activate IRF3 and induce IFNβ. These antiviral responses were also abolished in cells lacking TRAF2, 5, and 6, but not in those lacking individual TRAF protein. These TRAF proteins catalyze ubiquitination reactions that recruit NEMO to the MAVS signaling complex, leading to the activation of IKK and TBK1. MAVS phosphorylation by the recruited kinases then brings IRF3 to the complex, where IRF3 is phosphorylated by TBK1. These results reveal that MAVS, through the recruitment of multiple E3 ligases, not only activate downstream kinases but also specifies IRF3 phosphorylation by TBK1.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc910559199
dc.identifier.urihttps://hdl.handle.net/2152.5/ETD-UTSWMED-2013-05-108
dc.identifier.urihttps://hdl.handle.net/2152.5/1580
dc.language.isoenen
dc.subjectAdaptor Proteins, Signal Transducingen
dc.subjectInterferon Regulatory Factor-3en
dc.subjectSignal Transductionen
dc.titleKey Roles of Ubiquitination and Phosphorylation in RIG-I/MAVS Viral Sensing Pathwayen
dc.typeThesisen
dc.type.materialTexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineGenetics and Developmenten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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