Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/120091
Title: DISCOVERY OF NOVEL REGULATORS OF TYPE-I INTERFERON RESPONSE
Authors: LAM IRIS WING TO
Keywords: Type-I IFN, TLR3, ubiquitin ligase, TRAF4
Issue Date: 22-Dec-2014
Citation: LAM IRIS WING TO (2014-12-22). DISCOVERY OF NOVEL REGULATORS OF TYPE-I INTERFERON RESPONSE. ScholarBank@NUS Repository.
Abstract: Innate-immune pattern-recognition-receptor TLR3 is critical for sensing RNA viruses, and triggering transcription of potent antiviral type-I interferons. While ubiquitination is well known to regulate interferon response, a genome-wide understanding of the role of ubiquitin ligases in TLR3 signaling is yet to be generated. To fill this knowledge-gap, the effect of ectopic expression of the human ubiquitin ligases and their adaptors (UBL/A) encoded in human genome on TLR3 mediated type-I interferon b (IFNb) response was assessed. In the first part of the study, HEK293T cells over-expressing each one of the UBL/A genes were generated, stimulated with TLR3 ligand Poly (I:C), and the IFNb gene transcription was determined using IFNb gene promoter driven GFP-reporter. Microscopy based data collection and analysis identified novel positive or negative regulator UBL/A genes of IFNb production. An over expression screen was then carried out to identify the genes that regulate the IFN production by modulating the cellular level of TLR3. The capacity of the identified gene to regulate IFNb response was subsequently validated with a gene knock-down approach. Finally, the mechanism by which one selected hit gene (TRAF4) regulates the IFN response was investigated. It was determined that TRAF4 interacted with TLR3, and promoted degradation of the TLR3. Furthermore, Sendai virus infection resulted in transcriptional upregulation of TRAF4. In summary, this thesis identified TRAF4 as a negative regulator of TLR3 mediated interefron response, through the regulation of TLR3 protein turnover. Thus, this study generated both a novel global as well as specific mechanistic understanding of the role of UBL/A genes in TLR3 signalling.
URI: http://scholarbank.nus.edu.sg/handle/10635/120091
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