Identification and characterization of innate immune receptor substrates of γ-secretase enzyme complex

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dc.contributor.advisor McCarthy, Justin V. en Chhibber, Jyoti 2014-04-02T14:42:33Z 2013 2013
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.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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Jyoti Chhibber en
dc.rights.uri 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.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
dc.internal.availability Full text available en
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en Biochemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.embargoformat Both hard copy thesis and e-thesis en
dc.internal.conferring Summer Conferring 2014

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