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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
| dc.contributor.author | Yi-Hui Lai | en |
| dc.contributor.author | 賴怡惠 | zh_TW |
| dc.date.accessioned | 2021-06-16T05:24:19Z | - |
| dc.date.available | 2019-10-09 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-15 | |
| dc.identifier.citation | Chen, G. & Pedra, J. H. The inflammasome in host defense. Sensors (Basel) 10, 97-111, doi:10.3390/s100100097 (2010).
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56343 | - |
| dc.description.abstract | 發炎小體(the inflammasomes)為一蛋白質複合體，其功能為將第一型半胱天冬酶(caspase-1)活化並因此催化第一型介白素 β (IL-1β)與第十八型介白素(IL-18)的成熟。發炎小體適度的活化可清除病原體，但失控的發炎反應已被報導和許多癌症及自體炎症性疾病相關。我們實驗室發現了第二型纖溶酶原激活物抑制酶(PAI-2)能在受LPS刺激的巨噬細胞中抑制第一型介白素β的成熟。我們實驗室進行了酵母雙雜交實驗發現一核醣核酸解旋脢(DDX)為PAI-2的結合蛋白。然而，DDX在調控發炎小體的角色仍是未知的。我們研究發現當利用RNA干擾技術(RNA interference)抑制DDX的基因表現並處以細菌內毒素脂多醣體 (LPS，Lipopolysaccharide)後，不管是在人類巨噬細胞THP-1細胞株或是小鼠骨髓細胞分化成的巨噬細胞(BMDM)中都大幅提高成熟型第一型半胱天冬酶活性以及成熟型第一型介白素β的釋放。此外THP-1細胞在處以LPS後DDX會從細胞核轉到細胞質，而DDX的出核對它抑制發炎小體是很重要的。在人類胚腎細胞株HEK293T內證實DDX會和其中一種發炎小體蛋白NLRP3的LRR區域結合。因為LRR區域對於NLRP3跑到粒線體並結合接合蛋白ASC，我們發現NLRP3和ASC的結合會受到DDX存在下的干擾。這些研究結果證實DDX能夠負調控NLRP3發炎小體複合體的形成進而抑制第一型半胱天冬酶活性以及成熟型第一型介白素β的活性。 | zh_TW |
| dc.description.abstract | Inflammasome, a multiple protein complex modulating caspase-1 activity, regulates the proteolytic cleavage of proinflammatory cytokines, IL-1 sand IL-18, into their active forms. Inflammasomes play a crucial role in the clearance of pathogens, however, deregulated inflammasome activity contributes the pathogenesis of various diseases including auto-inflammatory diseases and cancers. Our previous studies showed that PAI-2 is a negative regulator of NLRP3 inflammasome activation. We previously identified a novel DEAD box-containing protein, DDX, using PAI-2 as a bait in a yeast two-hybrid screening. However, the role of DDX in regulation of the inlammasome activation remains unknown. In this research, we found that caspase-1 activation and mature IL-1β s production were largely enhanced upon LPS challenge in DDX-silenced THP-1 macrophages and bone marrow derived macrophages (BMDMs). In addition, DDX migrated from the nucleus to the cytoplasm upon LPS stimulation, which is required for its inhibitory role in NLRP3 inflammasome activation. DDX specifically interacted with the LRR motif of NLRP3 via its DEAD domain. Furthermore, due to the crucial role of the NLRP3 LRR domain in recruitment of NLRP3 to mitochondria and binding to its adaptor ASC, we found that the interaction of NLRP3 and ASC was downregulated in the presence of DDX. Our results suggest that DDX suppresses the formation of the NLRP3 inflammasome complex leading to negative regulation of caspase-1 activation and IL-1β s production. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T05:24:19Z (GMT). No. of bitstreams: 1 ntu-103-R01448008-1.pdf: 2952684 bytes, checksum: 18f3bf61031fddcf5d3d75528537d2dd (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 致謝 1
摘要 2 Abstract 3 Contents 5 Introduction 8 Inflammasomes 8 Classes of the inflammasomes 9 NLRP1 inflammasome 10 NLRP6 and NLRP12 inflammasomes 11 NLRC4 inflammasome 11 PYHIN inflammasome 12 NLRP3 inflammasome and its regulations 13 NLRP3 inflammasome and mitochondria 17 PAI-2 18 DEAD RNA Helicase family 19 The DEAD-box proteins and the immune system 20 DDX 21 Specific aim 23 Materials and Methods 24 Reagents 24 Plasmids 25 Site-directed mutagenesis 27 Cell culture and transfection 27 Preparation of pseudotyped lentiviruses 28 Preparation of Bone Marrow Derived Macrophages (BMDMs) 29 Preparation of whole cell lysate 30 Preparation of nuclear and cytosolic extracts 30 Immunoblotting 31 Detection of secreted cytokines and caspase-1 32 Immunoprecipitation 32 Immunofluorescence staining 33 Reconstitution of NLRP3 inflammasome in HEK293T cells 34 Purification of His-tagged DDX Antigen 34 DDX Antibody Production and Purification of DDX Antibody 36 Results 37 1. Generation of the DDX antibody 37 2. DDX depletion enhanced inflammasome activity and IL-1β production in THP-1 macrophages upon LPS treatment 39 3. Depletion of DDX in BMDMs induced caspase-1 activation and IL-1β production after LPS stimulation 40 4. DDX associated with NLRP3 in HEK293T and THP-1 macrophages 41 5. The DEAD domain of DDX associated with the LRR region of NLRP3. 41 6. Full length and the DEAD-box domain of DDX inhibited mature IL-1β production in reconstituted NLRP3 inflammasome. 43 7. DDX inhibited the interaction between NLRP3 and ASC in HEK293T cells. 44 8. DDX translocated to the cytosol in THP-1 macrophages in response to LPS. 44 9. Translocation of DDX to cytosol in LPS-treated THP-1 macrophages is required for DDX-mediated suppression of caspase-1 activation and IL-1β production. 46 Discussion 48 Figures 56 Figure 1. Expression and purification of a recombinant DDX polypeptide in E. coli. 56 Figure 2. Characterization of the specificity of homemade DDX antibody. 58 Figure 3.Knockdown of DDX in THP-1 macrophages enhanced IL-1β and IL-18 production and inflammasome activity after LPS stimulation. 59 Figure 4. Knockdown of DDX induced caspase-1 activation and IL-1β production in BMDMs after LPS stimulation. 60 Figure 5. DDX specifically associated with NLRP3 but not other NLRs or AIM2 in HEK293T cells. 61 Figure 6. The LRR of NLRP3 associated with DDX when overexpressed in HEK293T cells. 63 Figure 7. The DEAD domain of DDX associated with NLRP3. 64 Figure 8. Full length and the DEAD-box domain of DDX suppressed mature IL-1β production in the reconstituted with the NLRP3 inflammasome in HEK293T cells. 65 Figure 9. DDX blocked association of NLRP3 with ASC in HEK293T cells. 66 Figure 10. LPS induced translocation of wild type, but not DDX NES mutant, from the nucleus to the cytosol in THP-1 macrophages. 68 Figure 11. LPS-induced translocation of DDX to cytosol in THP-1 macrophages is required for DDX-mediated suppression of IL-1β production. 69 Reference 70 | |
| dc.language.iso | en | |
| dc.subject | 發炎小體 | zh_TW |
| dc.subject | inflammasome | en |
| dc.title | 一個新穎的DEAD-box蛋白於NLRP3發炎小體中的角色 | zh_TW |
| dc.title | The role of a novel DEAD-box containing protein in NLRP3 inflammasome activation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 莊雅惠(Ya-Hui chuang),陳俊任(Chun-Jen Chen) | |
| dc.subject.keyword | 發炎小體, | zh_TW |
| dc.subject.keyword | inflammasome, | en |
| dc.relation.page | 75 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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