Structural Basis for the Activation of RIG-I/MAVS Antiviral Immune Signaling

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dc.contributor.advisorRice, Luke M.en
dc.contributor.committeeMemberChen, Zhijian J.en
dc.contributor.committeeMemberJiang, Qiu-Xingen
dc.contributor.committeeMemberRosen, Michael K.en
dc.contributor.committeeMemberLiu, Qinghuaen
dc.creatorXu, Huien
dc.date.accessioned2017-06-02T15:28:28Z
dc.date.available2017-06-02T15:28:28Z
dc.date.created2015-05
dc.date.issued2015-04-09
dc.date.submittedMay 2015
dc.date.updated2017-06-02T15:15:17Z
dc.descriptionThe file named "XU-DISSERTATION-2015.pdf" is the primary dissertation file. The supplemental file named "Movie 1.mp4" may be viewed individually.en
dc.description.abstractRetinoic acid inducible gene-I (RIG-I) is a key cytosolic pathogen RNA sensor that activates mitochondrial antiviral signaling protein (MAVS) to trigger rapid innate immune responses. Using RNAs of different lengths as model ligands, we showed that RIG-I oligomerized on dsRNA in an ATP hydrolysis-dependent and dsRNA length-dependent manner, which correlated with the strength of type-I interferon (IFN-I) activation. The obtained negative stain EM structure of full-length RIG-I in complex with a 5'ppp stem-loop RNA and the crystal structure of RIG-I/Ub complex elucidated a two-step oligomerization and conformational change of RIG-I for activation. RIG-I oligomers nucleate MAVS through homotypic interaction of the N-terminal caspase activation and recruitment domains (CARDs) and induce the formation of prion-like aggregates. The obtained cryoEM structure of left-handed helical filaments of MAVS CARD revealed specific interfaces between individual CARD subunits that are dictated by a combination of electrostatic and hydrophobic interactions and hydrogen bonding. Point mutations at multiple locations of these interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed rod-shaped MAVS clusters on mitochondria. These results elucidated the structural mechanism of RIG-I activation by RNA and K63-linked ubiquitin chains as well as the activation of MAVS through polymerization, revealing a highly efficient signaling cascade for viral RNA sensing.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc988778264
dc.identifier.urihttps://hdl.handle.net/2152.5/4129
dc.language.isoenen
dc.subjectAdaptor Proteins, Signal Transducingen
dc.subjectImmunity, Innateen
dc.subjectMitochondriaen
dc.subjectRNA, Viralen
dc.titleStructural Basis for the Activation of RIG-I/MAVS Antiviral Immune Signalingen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineMolecular Biophysicsen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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