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系統識別號 U0026-2108201912103000
論文名稱(中文) TAPE-L (TAPE-like) 分子在Toll-like接受體訊號傳遞以及細菌感染的角色
論文名稱(英文) Roles of TAPE-L adaptor in Toll-like receptor signaling and bacterial infections
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 107
學期 2
出版年 108
研究生(中文) 葉正偉
研究生(英文) Zheng-Wei Yeh
學號 S46041024
學位類別 碩士
語文別 中文
論文頁數 39頁
口試委員 指導教授-凌斌
口試委員-鄧景浩
口試委員-羅玉枝
口試委員-李互暉
中文關鍵字 TAPE-L  TLR-MyD88 路徑  泛素化  細菌感染  NF-κB 活化 
英文關鍵字 TAPE-L  TLR-MyD88 pathways  ubiquitination  bacterial infections  NF-κB activation 
學科別分類
中文摘要 Toll-like 接受體 (TLRs) 是PRRs相當代表性的家族,可以辨認許多來自微生物的成分進而誘發先天免疫訊號。許多研究致力於探討TLR如何活化先天性免疫,先前我們實驗室發現了一種先天免疫調控蛋白TAPE (TBK-1 associated protein in endolysosome)。TAPE已被發現可以調控胞內體 TLR3, TLR4, and 細胞質RLR訊號路徑。在人類和小鼠基因組裡,一種 TAPE的同源基因稱作 TAPE-like
(TAPE-L) 已被發現。我們實驗室先前研究指出TAPE-L參與在RLR路徑以抵抗病毒感染,也可聯繫TLR路徑活化NF-κB 以產生發炎細胞激素。延續之前的成果,我有兩個研究方向。第一個方向是研究TAPE-L具體是如何調控TLR- NF-κB 路徑。我的資料顯示TAPE-L在TLR- NF-κB 路徑位於TRAF6和NEMO complex 之間。另一個發現是TAPE-L不會調節 TRAF6的K63泛素化。未來則會探討TAPE-L是否有調控NEMO泛素化的功能。除了NF-κB 活化,我也探討TAPE-L 是否涉及MAPK 分子在TLR路徑的活化.。比較 IκB 分解以活化NF-κB和 ERK-1/2 磷酸化,我發現TAPE-L只調節NF-κB活化;然而TAPE-L卻不會影響ERK-1/2活化。第二個方向是更進一步了解TAPE-L 在TLR路徑以及受細菌感染的功能性角色。利用基因剔除方法研究,我得出的結果是TAPE-L缺乏的小鼠巨噬細胞和纖維母細胞,無論在TLR配體刺激或是革蘭氏陰性細菌,IL-6的活化都有缺陷。此外,TAPE-L不足的小鼠受沙門桿菌感染時,生存狀況變差。除了上述得到的資訊,將來會更詳細探討TAPE-L對於清除體內或細胞內細菌的角色。
英文摘要 Abstract
Toll-like receptors (TLRs) represent a prototype family of PRRs that can detect a variety of microbial components to trigger innate immune signals. Significant progress has been made in studying TLRs signaling pathways to activate innate immunity. Previous studies in our lab discovered an innate immune regulator , called TAPE (TBK-1 associated protein in endolysosome). TAPE is shown to regulate the endosomal TLR3, TLR4, and cytoplasmic RIG-I-like receptor signaling pathways. A TAPE paralog in the human and mouse genomes was found, called TAPE-like (TAPE-L). Previous findings from our lab showed that TAPE-L was involved in the RLR pathway to defend viral infections, TAPE-L was also found linking surface TLR pathways to NF-κB activation for proinflammatory cytokine production. To continue the effort, my current work focuses two specific aims. My Specific Aim 1 is to study the underlying mechanism of how TAPE-L regulates the TLR- NF-κB pathway. My recent data showed that the position of TAPE-L locates between TRAF6 and NEMO complex in TLR-MyD88 pathways. Another finding is that TAPE-L does not K63 ubiquitination of TRAF6. Future work will determine whether TAPE-L regulates linear ubiquitination of NEMO. In addition to TLR-NF-κB axis, I am also studying on the role of TAPE-L in TLR-MAPK axis. By comparing IκB degradation for NF-κB activation and ERK-1/2 phosphorylation, I found that TAPE-L regulates NF-κB activation in TLR- MyD88 pathways; however, TAPE-L does not influence ERK-1/2 phosphorylation. The Specific Aim 2 is to further study the functional role of TAPE-L in the TLR pathways and bacterial infections by the genetic knockout approach. My preliminary data showed that TAPE-L deficient macrophages and fibroblasts were defective in IL-6 production upon TLR ligand stimulation or Gram-negative bacterial infections. TAPE-L deficient mice showed a poor survival rate during Salmonella infection. In addition to confirming the functional role of TAPE-L in TLR ligand stimulation, future studies will examine bacterial load in TAPE-L-deficient cells and mice.

Introduction
Pattern recognition receptors
Innate immunity is the first line of defense pathogen infections. Pattern recognition receptors (PRRs) in the innate immune system function to from recognize molecules from pathogens called pathogen-associated molecular patterns (PAMPs). After recognizing PAMPs, PRRs trigger downstream signals to the production of inflammatory cytokines and type I interferon production. Innate immune responses cause vasodilation, vascular permeability, maturation of immune cells like macrophage and dendritic cells (DCs) link innate immunity to adaptive immunity. Several PRR families are identified in the mammalian innate immune system, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), cell surface C-type lectin receptors (CLRs) and cytosolic DNA receptors like DDX41, STING.

Toll-like receptors
Mammalian TLRs are homolog of Drosophila melanogaster Toll-receptor, so far, 10 human TLRs and 12 mouse TLRs are identified. TLRs consist of an extracellular N-terminal leucine-rich repeats (LRRs), a transmembrance domain and a cytosolic C-terminal Toll/IL-1R homology domain (TIR domain). Cell surface TLRs include TLR1, TLR2, TLR4, TLR5, TLR6, they recognize bacterial ligands like lipoprotein, peptidoglycan, flagellin, LPS. Endosomal TLRs include TLR3, TLR7, TLR8, TLR9, they recognize DNA or RNA from pathogens. Upon recognizing their specific PAMPs, TLRs form homodimers or heterodimers. For example, TLR1 and TLR2 form heterodimer to bind triacyl lipoprotein, TLR4 not only forms homodimer but also needs CD14 and MD2 to bind LPS.

TLRs signaling pathways
TLRs, except TLR3, transduce signal by adaptor protein MyD88 for activation of NF-κB, AP-1, and IRF7. TIR domain of TLRs interacts with TIR domain of MyD88, and MyD88 recruits IRAK family members like IRAK1, IRAK2, IRAK4 to form myddosome complex. Myddosome complex interacts with TRAF6 and activate E3 ligase function of TRAF6. TRAF6 assembles K63 polyubiquitination chains with IRAK complex and other E3 ligase like Pellino 1 and 2. The E2 ligase complex Uev1A:Ubc13 binds K63 ubiquitin chains to activated TRAF6 or downstream molecule NEMO. Activated TRAF6 or free ubiquitin chain recruits TAB1 and TAB2/3 to recruit TAK1 for further signal transduction. Downstream of TAK1, TLR pathways activate NF-κB and AP-1 in different methods. For NF-κB activation, TAK1 recruits and activates IKK complex, IKKγ in IKK complex binds with linear polyubiquitination chains while IKKα and IKKβ are activated by phosphorylation. Then, IκB that binds with NF-κB with be degraded by K48 ubiquitination and NF-κB enters in nuclear for inflammatory cytokine productions. For AP-1 activation, TAK1 transduces signal to MAPKKs, phosphorylated MAPKKs transduce signal to MAPKs, phosphorylated activate AP-1, AP-1 enters in nuclear for inflammatory cytokine productions.

Ubiquitination in TLR-MyD88 pathways
Ubiquitin is a small protein that exists universally in eukaryotic cells. Ubiquitination is the posttranslational modification that ubiquitin is covalently bound to substrate protein with the E1-E2-E3 enzymatic cascade. Ubiquitin includes 7 lysine residues (K6, K11, K27, K29, K33, K48, K63) and 1 methionine residue (M1) for linkage of different polyubiquitin chains. According to the linkage of ubiquitination chains, it regulates substrate proteins to different biological functions. K48 ubiquitination drives substrate protein for degradation, K63 and M1 ubiquitination trigger substrate protein to signal transduction. TRAF6 K63 ubiquitination and NEMO linear ubiquitination are both essential in TLR-MyD88 signaling pathways for NF-κB activation . TRAF6 is activated by oligomerization through CC domain, CC domain also interacts with E2 ligase complex Uev1A:Ubc13. Zn domain of TRAF6 acts as E3 ligase to bind K63 polyubiquitination chains on itself. CC2 and LZ domain of NEMO, or CoZi domain, bind to linear ubiquitin chains. LUBAC complex produces M1-linked linear ubiquitination chains and HOIP of LUBAC acts as E3 ligase that binds linear ubiquitination chains to CoZi domain of NEMO.

The TLR-MyD88 pathways and diseases
TLR-MyD88 pathways play the essential role in defense of bacterial infections, deficiency and mutation of any molecules in TLR pathways impair signal cascades and defect immune responses. Clinical studies showed that patients with deficiencies in TLR pathways cause decreased IL-6 production and pyrogenic bacterial infection like S. aureus, S. pneumoniae, P. aeruginosa. Also, inflammatory diseases like pneumonia, meningitis, sepsis occur.

Roles of TAPE and TAPE-L in innate immunity
TAPE (TBK-1-associated protein in endolysosomes), or called as cc2d1a/Freud-1/Aki, is TBK-1-interacting protein located in endolysosomes. Previous studies in our lab showed that TAPE participates in various of innate immunity pathways. TAPE regulates RLR pathway to IFN-β activation against viral infections, TAPE also links TLR3 pathway to type I interferon production against EV71 infection. TAPE is involved in NOD2 pathway and NLRP3 inflammasome activation against bacterial infections as well. TAPE-L, also known as cc2d1b/Freud-2, is the paralog of TAPE. Studies in our lab found that TAPE-L can activate NF-κB and IFN-β. Also, TAPE-L is involved in RLR pathway and links surface TLR pathways to NF-κB activation. In surface TLR pathways, TAPE-L locates downstream of MyD88. Also, TAPE-L is suggested to regulates inflammatory cytokines production in THP-1 cell and regulates inflammatory response in vivo. Given these data, we further discover mechanistic roles of TAPE-L in surface TLR pathways and whether TAPE-L is essential in inflammatory cytokine production ex vivo and protects hosts against bacterial infections.
CONCLUSION
First, we focus on mapping the location of TAPE-L in surface TLR pathways. By comparison of NF-κB activation between WT and TAPE-L KO 293T cells with reporter assay, we found that TAPE-L may locate between TRAF6 and IKK complex nearby TARF6 or. Also, results show that TAPE-L does not regulate neither TRAF6 K63 ubiquitination nor MAPKs phosphorylation. We determine that TAPE-L locates between TRAF6 and IKK complex in TLR pathways and does not regulate MAPK activation. In functional roles of TAPE-L ex vivo, both TAPE-L KO MEFs and BMDMs impair inflammatory cytokines production under stimulations and infections. In functional roles of TAPE-L in vivo, data showed that TAPE-L protects survival of mice against bacterial infection; however, TAPE-L does not show significant effect of bacterial clearance in mice. Together, our works further show roles of TAPE-L in regulation of surface TLR pathways signaling under bacterial infections.
論文目次 Table of contents
摘要 I
Abstract II
誌謝 VII
Table of contents VIII
List of figures X
1. Introduction 1
1.1 Pattern recognition receptors…………………………………………………....1
1.2 Toll-like receptors 1
1.3 TLR signaling pathways 2
1.4 Ubiquitination in TLR-MyD88 pathways 3
1.5 Role of TAPE in the RIG-I signaling pathway 4
1.6 Roles of TAPE and TAPE-L in innate immunity 5
2. Materials…………………………………………………………………………7
3. Methods 11
3.1 Bacterial strains 11
3.2 Cell culture and reagents 11
3.3 Generation of HEK293T-TAPE-L CRISPR cells 11
3.4 Isolation and differentiation of bone marrow derived mavrophages 12
3.5 Enzyme-linked immunosorbent assay (ELISA) 12
3.6 Luciferase reporter assay 12
3.7 Co-immunoprecipitation and Western blotting 13
3.8 Animal infection……………………………………………………………….13
3.9 Isolation and differentiation of peritoneal macrophages 14
4. Results 15
4.1 The location of TAPE-L in TLR pathways .. 15
4.2 TAPE-L does not affects TRAF6 ubiquitination in TLR pathways.. 15
4.3 TAPE-L is not required for TLR4 signaling to MAPK activation. 16
4.4 TAPE-L is essential for TLR-mediated inflammatory cytokine production in primary cells under stimulations... 17
4.5 TAPE-L is essential for TLR-mediated inflammatory cytokine production in primary cells under infections.   17
4.6 TAPE-L protects against bacterial infections in vivo. 18
5. Discussion 19
6. References 22
7. Figures and Figure legends 28
8. Appendixes 38
參考文獻 1. Janeway, C.A. Approaching the asymptote? Evolution and revolution in immunology. in Cold Spring Harbor symposia on quantitative biology. 1989. Cold Spring Harbor Laboratory Press.
2. Medzhitov, R. and C.A. Janeway Jr, Innate immunity: impact on the adaptive immune response. Current opinion in immunology, 1997. 9(1): p. 4-9.
3. Newton, K. and V.M. Dixit, Signaling in innate immunity and inflammation. Cold Spring Harbor perspectives in biology, 2012. 4(3): p. a006049.
4. Iwasaki, A. and R. Medzhitov, Control of adaptive immunity by the innate immune system. Nat Immunol, 2015. 16(4): p. 343-53.
5. Hunter, C.A. and S.A. Jones, IL-6 as a keystone cytokine in health and disease. Nat Immunol, 2015. 16(5): p. 448-57.
6. Zhang, Z., et al., The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nature immunology, 2011. 12(10): p. 959.
7. Hansen, K., et al., Listeria monocytogenes induces IFNβ expression through an IFI16‐, cGAS‐and STING‐dependent pathway. The EMBO journal, 2014. 33(15): p. 1654-1666.
8. Xiao, T.S. and K.A. Fitzgerald, The cGAS-STING pathway for DNA sensing. Molecular cell, 2013. 51(2): p. 135-139.
9. Chen, Q., L. Sun, and Z.J. Chen, Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nature immunology, 2016. 17(10): p. 1142.
10. Bhat, N. and K.A. Fitzgerald, Recognition of cytosolic DNA by c GAS and other STING‐dependent sensors. European journal of immunology, 2014. 44(3): p. 634-640.
11. Bruno Lemaitre, E.N., Lydia Michaut, and a.J.A.H. Jean-Marc Reichhart, The Dorsoventral Regulatory Gene Cassette spa¨tzle/Toll/cactus Controls the Potent Antifungal Response in Drosophila Adults. Cell, 1996. Vol. 86, : p. 973–983.
12. Kawai, T. and S. Akira, The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol, 2009. 21(4): p. 317-37.
13. Vidya, M.K., et al., Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol, 2018. 37(1): p. 20-36.
14. Botos, I., D.M. Segal, and D.R. Davies, The structural biology of Toll-like receptors. Structure, 2011. 19(4): p. 447-59.
15. Du, B., et al., Targeting Toll-like receptors against cancer. Journal of Cancer Metastasis and Treatment, 2016. 2(12).
16. Li, K., et al., Promising Targets for Cancer Immunotherapy: TLRs, RLRs, and STING-Mediated Innate Immune Pathways. Int J Mol Sci, 2017. 18(2).
17. Lin, S.C., Y.C. Lo, and H. Wu, Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature, 2010. 465(7300): p. 885-90.
18. Sun, J.L.a.P.D., The Structure of the TLR5-Flagellin Complex: A New Mode of Pathogen Detection, Conserved Receptor Dimerization for Signaling. Sci Signal., 2012. 5(223): p. pe11.
19. Lim, K.H. and L.M. Staudt, Toll-like receptor signaling. Cold Spring Harb Perspect Biol, 2013. 5(1): p. a011247.
20. Zhang, Q., M.J. Lenardo, and D. Baltimore, 30 Years of NF-kappaB: A Blossoming of Relevance to Human Pathobiology. Cell, 2017. 168(1-2): p. 37-57.
21. Piras, V. and K. Selvarajoo, Beyond MyD88 and TRIF Pathways in Toll-Like Receptor Signaling. Front Immunol, 2014. 5: p. 70.
22. Chen, R.J.C.a.Y.H., Nuclear Factor-κB Activation and Regulation during Toll-Like. Cellular & Molecular Immunology., 2007. 4(1): p. 31-41.
23. De Nardo, D., et al., Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling. J Biol Chem, 2018. 293(39): p. 15195-15207.
24. Xie, P., TRAF molecules in cell signaling and in human diseases. Journal of Molecular Signaling, 2013. 8:7.
25. Fu, T.M., et al., Mechanism of ubiquitin transfer promoted by TRAF6. Proc Natl Acad Sci U S A, 2018. 115(8): p. 1783-1788.
26. Wertz, I.E. and V.M. Dixit, Signaling to NF-kappaB: regulation by ubiquitination. Cold Spring Harb Perspect Biol, 2010. 2(3): p. a003350.
27. Strickson, S., et al., Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling. Proc Natl Acad Sci U S A, 2017. 114(17): p. E3481-E3489.
28. Zinngrebe, J., et al., Ubiquitin in the immune system. EMBO Rep, 2014. 15(1): p. 28-45.
29. Hu, L., et al., Oligomerization-primed coiled-coil domain interaction with Ubc13 confers processivity to TRAF6 ubiquitin ligase activity. Nat Commun, 2017. 8(1): p. 814.
30. Hu, H. and S.C. Sun, Ubiquitin signaling in immune responses. Cell Res, 2016. 26(4): p. 457-83.
31. O'Neill, L.A., D. Golenbock, and A.G. Bowie, The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol, 2013. 13(6): p. 453-60.
32. Casanova, J.L., L. Abel, and L. Quintana-Murci, Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu Rev Immunol, 2011. 29: p. 447-91.
33. Dhillon, B., et al., The Evolving Role of TRAFs in Mediating Inflammatory Responses. Front Immunol, 2019. 10: p. 104.
34. Lopez-Castejon, G. and M.J. Edelmann, Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance? Mediators Inflamm, 2016. 2016: p. 3481371.
35. Talreja, J. and L. Samavati, K63-Linked Polyubiquitination on TRAF6 Regulates LPS-Mediated MAPK Activation, Cytokine Production, and Bacterial Clearance in Toll-Like Receptor 7/8 Primed Murine Macrophages. Front Immunol, 2018. 9: p. 279.
36. Israel, A., The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol, 2010. 2(3): p. a000158.
37. Kawasaki, T. and T. Kawai, Toll-like receptor signaling pathways. Front Immunol, 2014. 5: p. 461.
38. Maglione, P.J., N. Simchoni, and C. Cunningham-Rundles, Toll-like receptor signaling in primary immune deficiencies. Ann N Y Acad Sci, 2015. 1356: p. 1-21.
39. Liu, X., et al., Dynamic regulation of innate immunity by ubiquitin and ubiquitin-like proteins. Cytokine Growth Factor Rev, 2013. 24(6): p. 559-70.
40. Yunbing Wu, J.K., Lu Zhang, Zhaofeng Liang, Xudong Tang, Yongmin Yan, Hui Qian, Xu Zhang, Wenrong Xu, Fei Mao, Ubiquitination regulation of inflammatory responses through NF-κB pathway. Am J Transl Res 2018. 10(3): p. 881-891.
41. Courtois, G. and M.O. Fauvarque, The Many Roles of Ubiquitin in NF-kappaB Signaling. Biomedicines, 2018. 6(2).
42. Spit, M., E. Rieser, and H. Walczak, Linear ubiquitination at a glance. J Cell Sci, 2019. 132(2).
43. Walsh, M.C., J. Lee, and Y. Choi, Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev, 2015. 266(1): p. 72-92.
44. Elliott, P.R., Molecular basis for specificity of the Met1-linked polyubiquitin signal. Biochem Soc Trans, 2016. 44(6): p. 1581-1602.
45. Clark, K., S. Nanda, and P. Cohen, Molecular control of the NEMO family of ubiquitin-binding proteins. Nat Rev Mol Cell Biol, 2013. 14(10): p. 673-85.
46. Fujita, H., et al., Mechanism underlying IkappaB kinase activation mediated by the linear ubiquitin chain assembly complex. Mol Cell Biol, 2014. 34(7): p. 1322-35.
47. Rahighi, S., et al., Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell, 2009. 136(6): p. 1098-109.
48. Zinngrebe, J. and H. Walczak, TLRs Go Linear - On the Ubiquitin Edge. Trends Mol Med, 2017. 23(4): p. 296-309.
49. Wang, Y.Y., Y. Ran, and H.B. Shu, Linear ubiquitination of NEMO brakes the antiviral response. Cell Host Microbe, 2012. 12(2): p. 129-31.
50. Picard, C., J.L. Casanova, and A. Puel, Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin Microbiol Rev, 2011. 24(3): p. 490-7.
51. Frans, G., et al., Clinical characteristics of patients with low functional IL-6 production upon TLR/IL-1R stimulation. J Allergy Clin Immunol, 2018. 141(2): p. 768-770.
52. Picard, C., et al., Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore), 2010. 89(6): p. 403-25.
53. Fournier, B., The function of TLR2 during staphylococcal diseases. Front Cell Infect Microbiol, 2012. 2: p. 167.
54. Gobin, K., et al., IRAK4 Deficiency in a Patient with Recurrent Pneumococcal Infections: Case Report and Review of the Literature. Front Pediatr, 2017. 5: p. 83.
55. Baral, P., et al., Divergent functions of Toll-like receptors during bacterial lung infections. Am J Respir Crit Care Med, 2014. 190(7): p. 722-32.
56. Zhao, M., X.-D. Li, and Z. Chen, CC2D1A, a DM14 and C2 domain protein, activates NF-κB through the canonical pathway. Journal of Biological Chemistry, 2010. 285(32): p. 24372-24380.
57. Hadjighassem, M.R., et al., Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression. Biol Psychiatry, 2009. 66(3): p. 214-22.
58. Rogaeva, A., K. Galaraga, and P.R. Albert, The Freud‐1/CC2D1A family: Transcriptional regulators implicated in mental retardation. Journal of neuroscience research, 2007. 85(13): p. 2833-2838.
59. Zamarbide, M., et al., Loss of the Intellectual Disability and Autism Gene Cc2d1a and Its Homolog Cc2d1b Differentially Affect Spatial Memory, Anxiety, and Hyperactivity. Front Genet, 2018. 9: p. 65.
60. Martinelli, N., et al., CC2D1A is a regulator of ESCRT-III CHMP4B. Journal of molecular biology, 2012. 419(1-2): p. 75-88.
61. Usami, Y., et al., Regulation of CHMP4/ESCRT-III function in human immunodeficiency virus type 1 budding by CC2D1A. Journal of virology, 2012. 86(7): p. 3746-3756.
62. Jaekel, R. and T. Klein, The Drosophila Notch inhibitor and tumor suppressor gene lethal (2) giant discs encodes a conserved regulator of endosomal trafficking. Developmental cell, 2006. 11(5): p. 655-669.
63. Matsuda, A., et al., Large-scale identification and characterization of human genes that activate NF-κB and MAPK signaling pathways. Oncogene, 2003. 22(21): p. 3307.
64. Chen-Chu, K., Emerging roles ofTAPE innate immune adaptor in
inflammasome regulation and Gram-negative bacterial infection. 國立成功大學, 2015.
65. Chen, K.-R., Biochemical and functional study of antiviral innate immunity against RNA virus infection. 國立成功大學, 2015.
66. Wang, L.-C., Functional and mechanistic study of TAPE innate immune
regulator in the RIG-I-like receptor and endosomal Toll-like receptor pathways. 國立成功大學, 2017.
67. Drusenheimer, N., et al., The Mammalian Orthologs of Drosophila Lgd, CC2D1A and CC2D1B, Function in the Endocytic Pathway, but Their Individual Loss of Function Does Not Affect Notch Signalling. PLoS Genet, 2015. 11(12): p. e1005749.
68. Hadjighassem, M.R., K. Galaraga, and P.R. Albert, Freud-2/CC2D1B mediates dual repression of the serotonin-1A receptor gene. Eur J Neurosci, 2011. 33(2): p. 214-23.
69. McMillan, B.J., et al., Structural Basis for Regulation of ESCRT-III Complexes by Lgd. Cell Rep, 2017. 19(9): p. 1750-1757.
70. Ventimiglia, L.N., et al., CC2D1B Coordinates ESCRT-III Activity during the Mitotic Reformation of the Nuclear Envelope. Dev Cell, 2018. 47(5): p. 547-563 e6.
71. Vietri, M. and H. Stenmark, Orchestrating Nuclear Envelope Sealing during Mitosis. Dev Cell, 2018. 47(5): p. 541-542.
72. Lin, W.-Y., Characterization of a novel innate immune regulator, TAPE-L, in antiviral defenses. 國立成功大學, 2011.
73. Hsu, C.-L., Functional study of TAPE-like (TAPE-L) adaptor in innate immune regulation and bacterial infection. 國立成功大學, 2014.
74. Zurita, E., et al., Genetic polymorphisms among C57BL/6 mouse inbred strains. Transgenic research, 2011. 20(3): p. 481-489.
75. Simon, M.M., et al., A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome biology, 2013. 14(7): p. R82.
76. Cohen, P., The TLR and IL-1 signalling network at a glance. J Cell Sci, 2014. 127(Pt 11): p. 2383-90.
77. Liu, T., et al., NF-kappaB signaling in inflammation. Signal Transduct Target Ther, 2017. 2.
78. Meunier, E. and P. Broz, Evolutionary Convergence and Divergence in NLR Function and Structure. Trends Immunol, 2017. 38(10): p. 744-757.
79. Pashenkov, M.V., et al., Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications. J Leukoc Biol, 2019. 105(4): p. 669-680.
80. Bierschenk, D., D. Boucher, and K. Schroder, Salmonella-induced inflammasome activation in humans. Mol Immunol, 2017. 86: p. 38-43.
81. Keestra-Gounder, A.M., R.M. Tsolis, and A.J. Baumler, Now you see me, now you don't: the interaction of Salmonella with innate immune receptors. Nat Rev Microbiol, 2015. 13(4): p. 206-16.
82. Herhaus, L. and I. Dikic, Regulation of Salmonella-host cell interactions via the ubiquitin system. Int J Med Microbiol, 2018. 308(1): p. 176-184.
83. Wang, L., et al., Autophagy and Ubiquitination in Salmonella Infection and the Related Inflammatory Responses. Front Cell Infect Microbiol, 2018. 8: p. 78.
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