請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17835
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 徐立中 | |
dc.contributor.author | Hui-Mei Tsai | en |
dc.contributor.author | 蔡惠玫 | zh_TW |
dc.date.accessioned | 2021-06-08T00:44:24Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-06 | |
dc.identifier.citation | 1. Medzhitov, R. and C. Janeway, Jr., Innate immunity. N Engl J Med, 2000. 343(5): p. 338-44.
2. Janeway, C.A., Jr., Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol, 1989. 54 Pt 1: p. 1-13. 3. Matzinger, P., The danger model: a renewed sense of self. Science, 2002. 296(5566): p. 301-5. 4. Mogensen, T.H., Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev, 2009. 22(2): p. 240-73, Table of Contents. 5. Schattgen, S.A. and K.A. Fitzgerald, The PYHIN protein family as mediators of host defenses. Immunol Rev, 2011. 243(1): p. 109-18. 6. Akira, S. and K. Takeda, Toll-like receptor signalling. Nat Rev Immunol, 2004. 4(7): p. 499-511. 7. Beutler, B., Inferences, questions and possibilities in Toll-like receptor signalling. Nature, 2004. 430(6996): p. 257-63. 8. Janeway, C.A., Jr. and R. Medzhitov, Innate immune recognition. Annu Rev Immunol, 2002. 20: p. 197-216. 9. O'Neill, L.A. and A.G. Bowie, The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol, 2007. 7(5): p. 353-64. 10. Kawai, T. and S. Akira, The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol, 2010. 11(5): p. 373-84. 11. Opitz, B., et al., Role of Toll-like receptors, NOD-like receptors and RIG-I-like receptors in endothelial cells and systemic infections. Thromb Haemost, 2009. 102(6): p. 1103-9. 12. Ostuni, R., I. Zanoni, and F. Granucci, Deciphering the complexity of Toll-like receptor signaling. Cell Mol Life Sci, 2010. 67(24): p. 4109-34. 13. Iwasaki, A. and R. Medzhitov, Toll-like receptor control of the adaptive immune responses. Nat Immunol, 2004. 5(10): p. 987-95. 14. Carpenter, S. and L.A. O'Neill, Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins. Biochem J, 2009. 422(1): p. 1-10. 15. Jenkins, K.A. and A. Mansell, TIR-containing adaptors in Toll-like receptor signalling. Cytokine, 2010. 49(3): p. 237-44. 16. Horng, T., et al., The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature, 2002. 420(6913): p. 329-33. 17. Tanimura, N., et al., Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun, 2008. 368(1): p. 94-9. 18. Carty, M., et al., The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol, 2006. 7(10): p. 1074-81. 19. Kawai, T. and S. Akira, TLR signaling. Semin Immunol, 2007. 19(1): p. 24-32. 20. Hoebe, K., et al., Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature, 2003. 424(6950): p. 743-8. 21. Yamamoto, M., et al., Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol, 2002. 169(12): p. 6668-72. 22. Medzhitov, R., et al., MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell, 1998. 2(2): p. 253-8. 23. Gay, N.J., et al., Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol, 2014. 14(8): p. 546-58. 24. Motshwene, P.G., et al., An oligomeric signaling platform formed by the Toll-like receptor signal transducers MyD88 and IRAK-4. J Biol Chem, 2009. 284(37): p. 25404-11. 25. Wang, C., et al., TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature, 2001. 412(6844): p. 346-51. 26. Deng, L., et al., Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell, 2000. 103(2): p. 351-61. 27. Li, S., et al., IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A, 2002. 99(8): p. 5567-72. 28. Takeuchi, O. and S. Akira, Pattern recognition receptors and inflammation. Cell, 2010. 140(6): p. 805-20. 29. Yamamoto, M., et al., Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science, 2003. 301(5633): p. 640-3. 30. Meylan, E., et al., RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol, 2004. 5(5): p. 503-7. 31. Hacker, H. and M. Karin, Regulation and function of IKK and IKK-related kinases. Sci STKE, 2006. 2006(357): p. re13. 32. Oganesyan, G., et al., Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature, 2006. 439(7073): p. 208-11. 33. Barton, G.M. and J.C. Kagan, A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol, 2009. 9(8): p. 535-42. 34. Husebye, H., et al., The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. Immunity, 2010. 33(4): p. 583-96. 35. Inoue, J., et al., Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res, 2000. 254(1): p. 14-24. 36. Ha, H., D. Han, and Y. Choi, TRAF-mediated TNFR-family signaling. Curr Protoc Immunol, 2009. Chapter 11: p. Unit11.9D. 37. Hacker, H., P.H. Tseng, and M. Karin, Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol, 2011. 11(7): p. 457-68. 38. Mao, R., et al., TAK1 lysine 158 is required for TGF-beta-induced TRAF6-mediated Smad-independent IKK/NF-kappaB and JNK/AP-1 activation. Cell Signal, 2011. 23(1): p. 222-7. 39. Xie, P., et al., TNF receptor-associated factor 3 is required for T cell-mediated immunity and TCR/CD28 signaling. J Immunol, 2011. 186(1): p. 143-55. 40. Yang, C.H., et al., The role of TRAF2 binding to the type I interferon receptor in alternative NF kappaB activation and antiviral response. J Biol Chem, 2008. 283(21): p. 14309-16. 41. Zepp, J., L. Wu, and X. Li, IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease. Trends Immunol, 2011. 32(5): p. 232-9. 42. Wajant, H., F. Henkler, and P. Scheurich, The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators. Cell Signal, 2001. 13(6): p. 389-400. 43. Arron, J.R., M.C. Walsh, and Y. Choi, TRAF-mediated TNFR-family signaling. Curr Protoc Immunol, 2002. Chapter 11: p. Unit 11.9D. 44. Bhoj, V.G. and Z.J. Chen, Ubiquitylation in innate and adaptive immunity. Nature, 2009. 458(7237): p. 430-7. 45. Chau, V., et al., A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science, 1989. 243(4898): p. 1576-83. 46. Finley, D., et al., Inhibition of proteolysis and cell cycle progression in a multiubiquitination-deficient yeast mutant. Mol Cell Biol, 1994. 14(8): p. 5501-9. 47. Tseng, P.H., et al., Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol, 2010. 11(1): p. 70-5. 48. Hacker, H., et al., Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature, 2006. 439(7073): p. 204-7. 49. Matsuzawa, A., et al., Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science, 2008. 321(5889): p. 663-8. 50. Matthews, J.M. and M. Sunde, Zinc fingers--folds for many occasions. IUBMB Life, 2002. 54(6): p. 351-5. 51. Miller, J., A.D. McLachlan, and A. Klug, Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. Embo j, 1985. 4(6): p. 1609-14. 52. Krishna, S.S., I. Majumdar, and N.V. Grishin, Structural classification of zinc fingers: survey and summary. Nucleic Acids Res, 2003. 31(2): p. 532-50. 53. Matsushita, K., et al., Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature, 2009. 458(7242): p. 1185-90. 54. He, G., et al., The protein Zfand5 binds and stabilizes mRNAs with AU-rich elements in their 3'-untranslated regions. J Biol Chem, 2012. 287(30): p. 24967-77. 55. Lee, E.G., et al., Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science, 2000. 289(5488): p. 2350-4. 56. Huang, J., et al., ZNF216 Is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation. J Biol Chem, 2004. 279(16): p. 16847-53. 57. Hishiya, A., et al., A novel ubiquitin-binding protein ZNF216 functioning in muscle atrophy. Embo j, 2006. 25(3): p. 554-64. 58. Scott, D.A., et al., Identification and mutation analysis of a cochlear-expressed, zinc finger protein gene at the DFNB7/11 and dn hearing-loss loci on human chromosome 9q and mouse chromosome 19. Gene, 1998. 215(2): p. 461-9. 59. Hishiya, A., K. Ikeda, and K. Watanabe, A RANKL-inducible gene Znf216 in osteoclast differentiation. J Recept Signal Transduct Res, 2005. 25(3): p. 199-216. 60. Lin, Y.C., et al., The tyrosine kinase Syk differentially regulates Toll-like receptor signaling downstream of the adaptor molecules TRAF6 and TRAF3. Sci Signal, 2013. 6(289): p. ra71. 61. Chen, Y.-C., The functional role of a novel zinc finger protein in inflammation, in Institute of Molecular Medicine. 2012, National Taiwan University. 62. Lien, C.-I., The functional role of a novel zinc finger protein in the regulation of TLR4-mediated immune responses, in Institute of Molecular Medicine. 2014, National Taiwan University. 63. Akira, S., S. Uematsu, and O. Takeuchi, Pathogen recognition and innate immunity. Cell, 2006. 124(4): p. 783-801. 64. Foster, S.L., D.C. Hargreaves, and R. Medzhitov, Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature, 2007. 447(7147): p. 972-8. 65. Kagan, J.C., et al., TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol, 2008. 9(4): p. 361-8. 66. Tada, K., et al., Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death. J Biol Chem, 2001. 276(39): p. 36530-4. 67. Oeckinghaus, A., M.S. Hayden, and S. Ghosh, Crosstalk in NF-kappaB signaling pathways. Nat Immunol, 2011. 12(8): p. 695-708. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17835 | - |
dc.description.abstract | Innate immunity is the first-line defense of hosts to combat invading microbes and cellular damages. It is initiated by the activation of various germline-encoded pattern recognition receptors (PRRs) including Toll-lie receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), and PYHIN family. PRRs recognize pathogen-associated molecular patterns (PAMPs) derived from bacteria, viruses and fungi, and damage-associated molecular patterns (DAMPs) from stressed or injured tissues. Activation of TLRs elicits MyD88- and/or TRIF-dependent signaling pathways resulting in the induction of proinflammatory cytokines and type-I interferons. However, both under- or over-expression of these cytokines lead to infectious and inflammatory diseases, respectively, which are dangerous to hosts. Thus, tight regulation of TLRs-mediated immune responses is important. We previously identified a zinc-finger protein—ZFAND5 that was upregulated in LPS stimulated-macrophages. Here, we focused on its role in TLRs-mediated pathways and possible molecular mechanism. We found that the expression of inflammatory cytokines, and type I interferons and interferon-stimulated genes was reduced upon TLR1/2, TLR3, TLR4 and TLR9 activation in ZFAND5-deficient macrophages. Furthermore, ZFAND5 interacted with TRAF3 in response to LPS stimulation. Through domain mapping, we found that the A20-like domain of ZFNAD5 and the TRAF-C domain of TRAF3 were required for their interaction. Taken together, our studies revealed that ZFAND5 involves in TLRs-mediated immune responses possibly through TRAF3. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:44:24Z (GMT). No. of bitstreams: 1 ntu-104-R02448015-1.pdf: 2037079 bytes, checksum: e5bdf5b8398365c4e1d43bc64f2662d8 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 口試委員會審定書--------------------------------------------------------------------------- i
中文摘要---------------------------------------------------------------------------------------- ii Abstract------------------------------------------------------------------------------------------- iii Introduction 1-10 Innate immunity--------------------------------------------------------------------------- 1 Toll-like receptors (TLRs)--------------------------------------------------------------- 2 TLRs signaling pathways---------------------------------------------------------------- 2 TIR-domain-containing adaptors-------------------------------------------------- 2 Myddosome formation and MyD88-dependent pathway---------------------- 3 Triffosome formation and TRIF-dependent pathway--------------------------- 5 TLR4 signaling pathway----------------------------------------------------------- 5 TRAFs-------------------------------------------------------------------------------------- 6 TRAF3 in TLR4 signaling--------------------------------------------------------- 7 Zinc-finger containing proteins---------------------------------------------------------- 8 TLRs-inducible zinc-finger containing proteins-------------------------------- 8 ZFAND5------------------------------------------------------------------------------ 9 Specific aim-------------------------------------------------------------------------------------- 11 Materials and Methods 12-18 Antibodies---------------------------------------------------------------------------------- 12 Reagents------------------------------------------------------------------------------------ 12 Plasmids------------------------------------------------------------------------------------ 12 Cell culture--------------------------------------------------------------------------------- 13 Transfection-------------------------------------------------------------------------------- 13 Generation of ZFADN5-knockdown cells--------------------------------------------- 14 Generation of ZFAND5-knockout cells------------------------------------------------ 15 Preparation of whole cell lysate--------------------------------------------------------- 15 Immunoblotting---------------------------------------------------------------------------- 16 Immunoprecipitation---------------------------------------------------------------------- 16 Total RNA extraction--------------------------------------------------------------------- 16 Reverse Transcription Quantitative PCR (RT-qPCR)-------------------------------- 17 Statistical analysis------------------------------------------------------------------------- 18 Results 19-23 Depletion of ZFAND5 downregulated the mRNA expression of proinflammatory cytokines and interferon responsive genes upon LPS stimulation--------------------------------------------------------------------------------- 19 Depletion of ZFAND5 downregulated the mRNA expression of proinflammatory cytokines and interferon responsive genes upon TLR2/3/9, but not TNFα activation------------------------------------------------------------------ 20 ZFAND5 associated with TRAF3 through its N-terminal A20-like domain------ 21 TRAF3 associated with ZFAND5 through its C-terminal TRAF-C-domain------ 22 LPS induced the association of ZFAND5 and TRAF3------------------------------ 22 Discussion---------------------------------------------------------------------------------------- 24-29 Figures 30-48 Figure 1. ----------------------------------------------------------------------------------- 30 Figure 2. ----------------------------------------------------------------------------------- 32 Figure 3. ----------------------------------------------------------------------------------- 34 Figure 4. ----------------------------------------------------------------------------------- 35 Figure 5. ----------------------------------------------------------------------------------- 37 Figure 6. ----------------------------------------------------------------------------------- 38 Figure 7. ----------------------------------------------------------------------------------- 39 Figure 8. ----------------------------------------------------------------------------------- 40 Figure 9. ----------------------------------------------------------------------------------- 42 Figure 10.----------------------------------------------------------------------------------- 43 Figure 11. ---------------------------------------------------------------------------------- 45 Figure 12. ---------------------------------------------------------------------------------- 47 Supplementary Figure 1.………………………………………………………... 48 References---------------------------------------------------------------------------------------- 49-52 | |
dc.language.iso | en | |
dc.title | 一個新穎的鋅指蛋白在TLR4所扮演之功能探討 | zh_TW |
dc.title | The functional role of a novel zinc finger protein in the regulation of TLR4 signaling | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 盧主欽,胡孟君 | |
dc.subject.keyword | 先天免疫,鋅指蛋白, | zh_TW |
dc.subject.keyword | innate immunity,TLR, | en |
dc.relation.page | 52 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2015-08-07 | |
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 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-104-1.pdf 目前未授權公開取用 | 1.99 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。