Identification and characterization of innate immune receptor substrates of γ-secretase enzyme complex
| dc.check.embargoformat | Both hard copy thesis and e-thesis | en |
| dc.check.opt-out | Yes | en |
| dc.check.reason | This thesis is due for publication or the author is actively seeking to publish this material | en |
| dc.contributor.advisor | McCarthy, Justin V. | en |
| dc.contributor.author | Chhibber, Jyoti | |
| dc.contributor.funder | Science Foundation Ireland | en |
| dc.date.accessioned | 2014-04-02T14:42:33Z | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013 | |
| dc.description.abstract | The γ-secretase protease complexes and associated regulated intramembrane proteolysis play an important role in controlling receptor-mediated intracellular signalling events, which have a central role in Alzheimer’s disease, cancer progression and immune surveillance. It has previously been reported that the Interleukin-1 receptor, type 1, (IL-1R1) is a substrate for regulated intramembrane proteolysis, mediated by presenilin (PS)-dependent γ-secretase activity. The aims of this project were twofold. Firstly, to determine the conservation of regulated intramembrane proteolysis as a physiological occurrence amongst other cytokine receptors. In this regard, similar to IL-1R1, we identified the Tumour necrosis factor receptor type 1 (TNFR1) and the Toll like receptor 4 (TLR4) as novel γ-secretase substrates. Secondly, given that the diversity of signalling events mediated by the IL-1R1, TLR4 and TNFR1 are spatially segregated, we investigated the spatial distribution, subcellular trafficking and subcellular occurrence of regulated intramembrane proteolysis of IL-1R1, TLR4 and TNFR1. Using dynasore an inhibitor of clathrin-dependent receptor endocytosis, both ectodomain shedding and γ-secretase-mediated cleavage of IL-1R1 were observed post-internalization. In contrast, TNFR-1 underwent ectodomain shedding at the cell surface followed by endosomal γ-secretase-mediated cleavage. Furthermore, immortalised fibroblasts from PS1-deficient mice showed impaired γ-secretasemediated cleavage of IL-1R1 and TNFR1, indicating that both are cleaved by PS1-and not PS2-containing γ-secretase complexes. Subcellular fractionation and immunofluorescence studies revealed that the γ-secretase generated IL-1R1 ICD translocates to the nucleus on IL-1β stimulation. These observations further demonstrate the novel PS-dependent means of modulating IL-1β, LPS and TNFα- mediated immune responses by regulating IL-1R1/TLR4/TNFR1 protein levels within the cells. | en |
| dc.description.sponsorship | Science Foundation Ireland (SFI Grant 09/IN.1/B2624) | en |
| dc.description.status | Not peer reviewed | en |
| dc.description.version | Accepted Version | |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Chhibber, J. 2013. Identification and characterization of innate immune receptor substrates of γ-secretase enzyme complex. PhD Thesis, University College Cork. | en |
| dc.identifier.endpage | 203 | |
| dc.identifier.uri | https://hdl.handle.net/10468/1501 | |
| dc.language.iso | en | en |
| dc.publisher | University College Cork | en |
| dc.rights | © 2013, Jyoti Chhibber | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | en |
| dc.subject | IL-1R1 | en |
| dc.subject | TNFR1 | en |
| dc.subject | TLR4 | en |
| dc.subject | Presenilin | en |
| dc.subject | Regulated intramembrane proteolysis | en |
| dc.subject.lcsh | Presenilins | en |
| dc.subject.lcsh | Proteolytic enzymes | en |
| dc.subject.lcsh | Cytokines | en |
| dc.subject.lcsh | Receptors | en |
| dc.thesis.opt-out | true | |
| dc.title | Identification and characterization of innate immune receptor substrates of γ-secretase enzyme complex | en |
| dc.type | Doctoral thesis | en |
| dc.type.qualificationlevel | Doctoral | en |
| dc.type.qualificationname | PhD (Science) | en |
