Key Role of Lys63-Linked Polyubiquitination in Viral Activation of IRF3
| dc.contributor.advisor | Chen, Zhijian J. | en |
| dc.creator | Zeng, Wenwen | en |
| dc.date.accessioned | 2010-07-12T18:13:16Z | |
| dc.date.available | 2010-07-12T18:13:16Z | |
| dc.date.issued | 2009-06-19 | |
| dc.description.abstract | Viral nucleic acids exposed during invasion and proliferation are detected by mammalian cells through receptors belonging to pattern-recognition receptors family (PRRs). Among PRRs, RIG-I-like receptors (RLRs), including RIG-I, MDA5 and LGP2, are responsible for sensing intracellular viral RNAs. MAVS, a mitochondria-localized transmembrane protein, transduces signaling from RIG-I and MDA5 to activate downstream transcription factors IRF3 and NF-kB, which contribute to the induction of IFNb. Despite growing list of components revealed in RIG-I/MAVS/IRF3 pathway, molecular mechanism by which MAVS activates IRF3 upon viral infection has remained largely unclear. In current study, employing a cell-free system together with conventional fractionation procedures, Ubc5 was identified as a specific ubiquitin-conjugating enzyme (E2) involved in IRF3 activation. Taking advantages of inducible-RNAi strategy, catalytically active Ubc5 was shown to be essential for viral activation of IRF3. Furthermore, evidences were obtained indicating that Lys63-linked polyubiquitination played a key role in MAVS-mediated IRF3 activation both in vitro and in vivo. Finally, NEMO was demonstrated to function as a ubiquitin-chain adaptor recruiting and activating TBK1, the kinase for IRF3 phosphorylation. Those results offered insights into the mechanism underlying IRF3 activation mediated by K63-linked polyubiquitination. | en |
| dc.format.digitalOrigin | born digital | en |
| dc.format.medium | Electronic | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 754805403 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/482 | |
| dc.language.iso | en | en |
| dc.subject | Interferon Regulatory Factor-3 | en |
| dc.subject | Sendai virus | en |
| dc.subject | Virus Activation | en |
| dc.subject | Ubiquitin-Conjugating Enzymes | en |
| dc.title | Key Role of Lys63-Linked Polyubiquitination in Viral Activation of IRF3 | en |
| dc.type | Thesis | en |
| dc.type.genre | dissertation | en |
| dc.type.material | Text | en |
| thesis.date.available | 2011-06-19 | |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Genetics and Development | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |