過度的發炎反應會引起慢性或全身性炎症，但是發炎反應不足會導致病原體的持續感染。NLRP3發炎小體會透過反應來自宿主細胞或傳染性微生物的危險信號調節caspase-1的激活。活化的caspase-1產生活化的IL-1β和IL-18，以誘導下游的免疫反應，例如募集免疫細胞（如巨噬細胞和嗜中性粒細胞）來防禦感染性微生物。活化的caspase-1也會裂解Gasdermin D（GSDMD），以誘導炎症性細胞死亡，稱為細胞焦亡(pyroptosis)。我們以前的工作發現了一種稱為TAPE（TBK1-Associated Protein in Endolysosomes）的先天性免疫調節劑，可能與發炎小體的活化有關。最近的證據表明，蛋白激酶NEK7與NLRP3結合以促進NLRP3的寡聚，從而導致NLRP3發炎小體的活化。值得注意的是，另一項研究報導TAPE是一種與NEK7相互作用的蛋白。綜上所述，我的論文將聚焦於研究TAPE如何調節NLRP3炎性小體激活的分子機制。首先進行了生化分析，以評估TAPE對NLRP3發炎小體的作用。為了支持以前的ELISA數據，我的沉澱免疫印跡結果表明，在TAPE缺陷型巨噬細胞中，由nigericin或ATP誘導的IL-1β的釋放減少了。目標2是了解TAPE調控NLRP3發炎小體的分子機制。免疫共沉澱結果表明，NLPE3發炎小體激活後，TAPE與人單核細胞中的NLRP3有交互作用。 TAPE通過其N末端結構域與NLRP3結合，而NLRP3通過其PYD和LRR與TAPE相互作用。共聚焦顯微鏡分析表明，TAPE與NLRP3在轉染細胞或原代鼠巨噬細胞中共定位。為了評估TAPE在NLRP3發炎小體組裝中的作用，我們注意到TAPE-CRISPR HeLa細胞中NLRP3點的大小明顯小於親代HeLa細胞中的大小。在TAPE缺失的初級巨噬細胞中，ASC斑點的數量也顯著減少。非變性膠體電泳分析顯示，在TAPE-CRISPR細胞中含有NLRP3的大蛋白複合物大大減少，這表明TAPE是NLRP3組裝所必需的。總之，我的結果表明TAPE對於NLRP3發炎小體的組裝和激活至關重要。

Excessive inflammation causes chronic or systemic inflammatory diseases, but insufficient inflammation leads to persistent pathogen infection. The NLRP3 inflammasome regulates the activation of caspase-1 in response to danger signals from host cells or infectious microbes. Active caspase-1 generates active cytokines IL-1β and IL-18 to induce a downstream immune response, such as recruiting the immune cells like macrophages and neutrophils to defend against microbes. Active caspase-1 also cleaves Gasdermin D (GSDMD) to induce inflammatory cell death called pyroptosis. Our previous work revealed that an innate immune regulator, called TAPE (TBK1-Associated Protein in Endolysosomes), might involve in the activation of NLRP3 inflammasome. Recent evidence indicated that a protein kinase NEK7 binds to NLRP3 to promote the assembly and activation of NLRP3 inflammasome. Notably, another study reports that TAPE is a NEK7-interacting protein. Given these facts, my thesis work focused on investigating the molecular mechanisms of how TAPE regulates the activation of NLRP3 inflammasome as the following aims. First, further biochemical analyses were conducted to assess the TAPE effect on NLRP3 inflammasome. In support of previous ELISA data, my results from the precipitation-immunoblotting showed that the release of cleaved IL-1β induced by nigericin or ATP was decreased in TAPE –deficient macrophages. The Aim 2 was to gain mechanistic insights into the regulation of NLRP3 inflammasome by TAPE. Co-immunoprecipitation results showed that TAPE was associated with NLRP3 in human monocytic cells upon NLRP3 inflammasome activation. TAPE bound to NLRP3 via its N-terminal domain, while NLRP3 interacted with TAPE via its pyrin domain and leucine-rich repeats. Confocal microscopic analyses showed that TAPE was co-localized with NLRP3 in transfected cells or primary murine macrophages. To assess the role of TAPE in the assembly of NLRP3 inflammasome, we noticed that the size of NLRP3 puncta in TAPE-CRISPR HeLa cells is significantly smaller than those in parental HeLa cells. The numbers of ASC specks were also significantly decreased in TAPE-deficient primary macrophages. Native PAGE analyses showed that a large protein complex containing NLRP3 was greatly reduced in TAPE-CRISPR cells, suggesting that TAPE is required for the assembly of NLRP3. Together, my results demonstrate that TAPE is essential for NLRP3 inflammasome assembly and activation.

1. Paludan, S. R., and Bowie, A. G. (2013) Immune sensing of DNA. Immunity 38, 870-880
2. Takeuchi, O., and Akira, S. (2010) Pattern recognition receptors and inflammation. Cell 140, 805-820
3. Schroder, K., and Tschopp, J. (2010) The inflammasomes. Cell 140, 821-832
4. Chen, G., Shaw, M. H., Kim, Y. G., and Nunez, G. (2009) NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol 4, 365-398
5. Chamaillard, M., Hashimoto, M., Horie, Y., Masumoto, J., Qiu, S., Saab, L., Ogura, Y., Kawasaki, A., Fukase, K., Kusumoto, S., Valvano, M. A., Foster, S. J., Mak, T. W., Nuñez, G., and Inohara, N. (2003) An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nature Immunology 4, 702-707
6. Girardin, S. E., Boneca, I. G., Carneiro, L. A. M., Antignac, A., Jéhanno, M., Viala, J., Tedin, K., Taha, M.-K., Labigne, A., Zäthringer, U., Coyle, A. J., DiStefano, P. S., Bertin, J., Sansonetti, P. J., and Philpott, D. J. (2003) Nod1 Detects a Unique Muropeptide from Gram-Negative Bacterial Peptidoglycan. Science 300, 1584-1587
7. Caruso, R., Warner, N., Inohara, N., and Nunez, G. (2014) NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41, 898-908
8. Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., Binder, V., Finkel, Y., Cortot, A., Modigliani, R., Laurent-Puig, P., Gower-Rousseau, C., Macry, J., Colombel, J.-F., Sahbatou, M., and Thomas, G. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599-603
9. Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nuñez, G., and Cho, J. H. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603-606
10. Strowig, T., Henao-Mejia, J., Elinav, E., and Flavell, R. (2012) Inflammasomes in health and disease. Nature 481, 278-286
11. Howard, A. D., Kostura, M. J., Thornberry, N., Ding, G. J., Limjuco, G., Weidner, J., Salley, J. P., Hogquist, K. A., Chaplin, D. D., and Mumford, R. A. (1991) IL-1-converting enzyme requires aspartic acid residues for processing of the IL-1 beta precursor at two distinct sites and does not cleave 31-kDa IL-1 alpha. The Journal of Immunology 147, 2964-2969
12. Latz, E., Xiao, T. S., and Stutz, A. (2013) Activation and regulation of the inflammasomes. Nature Reviews Immunology 13, 397-411
13. Liu, X., Zhang, Z., Ruan, J., Pan, Y., Magupalli, V. G., Wu, H., and Lieberman, J. (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153-158
14. Kayagaki, N., Stowe, I. B., Lee, B. L., O'Rourke, K., Anderson, K., Warming, S., Cuellar, T., Haley, B., Roose-Girma, M., Phung, Q. T., Liu, P. S., Lill, J. R., Li, H., Wu, J., Kummerfeld, S., Zhang, J., Lee, W. P., Snipas, S. J., Salvesen, G. S., Morris, L. X., Fitzgerald, L., Zhang, Y., Bertram, E. M., Goodnow, C. C., and Dixit, V. M. (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666-671
15. Guo, H., Callaway, J. B., and Ting, J. P. (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21, 677-687
16. Bauernfeind, F. G., Horvath, G., Stutz, A., Alnemri, E. S., MacDonald, K., Speert, D., Fernandes-Alnemri, T., Wu, J., Monks, B. G., Fitzgerald, K. A., Hornung, V., and Latz, E. (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183, 787-791
17. Song, N., Liu, Z. S., Xue, W., Bai, Z. F., Wang, Q. Y., Dai, J., Liu, X., Huang, Y. J., Cai, H., Zhan, X. Y., Han, Q. Y., Wang, H., Chen, Y., Li, H. Y., Li, A. L., Zhang, X. M., Zhou, T., and Li, T. (2017) NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation. Mol Cell 68, 185-197 e186
18. Stutz, A., Kolbe, C. C., Stahl, R., Horvath, G. L., Franklin, B. S., van Ray, O., Brinkschulte, R., Geyer, M., Meissner, F., and Latz, E. (2017) NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J Exp Med 214, 1725-1736
19. Py, B. F., Kim, M. S., Vakifahmetoglu-Norberg, H., and Yuan, J. (2013) Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell 49, 331-338
20. Swanson, K. V., Deng, M., and Ting, J. P. (2019) The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19, 477-489
21. Vajjhala, P. R., Mirams, R. E., and Hill, J. M. (2012) Multiple binding sites on the pyrin domain of ASC protein allow self-association and interaction with NLRP3 protein. J Biol Chem 287, 41732-41743
22. Duncan, J. A., Bergstralh, D. T., Wang, Y., Willingham, S. B., Ye, Z., Zimmermann, A. G., and Ting, J. P. (2007) Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci U S A 104, 8041-8046
23. Hafner-Bratkovic, I., Susjan, P., Lainscek, D., Tapia-Abellan, A., Cerovic, K., Kadunc, L., Angosto-Bazarra, D., Pelegrin, P., and Jerala, R. (2018) NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway. Nat Commun 9, 5182
24. Mangan, M. S. J., Olhava, E. J., Roush, W. R., Seidel, H. M., Glick, G. D., and Latz, E. (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov 17, 588-606
25. Lu, A., Magupalli, V. G., Ruan, J., Yin, Q., Atianand, M. K., Vos, M. R., Schroder, G. F., Fitzgerald, K. A., Wu, H., and Egelman, E. H. (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156, 1193-1206
26. Cai, X., Chen, J., Xu, H., Liu, S., Jiang, Q. X., Halfmann, R., and Chen, Z. J. (2014) Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207-1222
27. Srinivasula, S. M., Poyet, J.-L., Razmara, M., Datta, P., Zhang, Z., and Alnemri, E. S. (2002) The PYRIN-CARD Protein ASC Is an Activating Adaptor for Caspase-1. Journal of Biological Chemistry 277, 21119-21122
28. Yang, X., Chang, H. Y., and Baltimore, D. (1998) Autoproteolytic Activation of Pro-Caspases by Oligomerization. Molecular Cell 1, 319-325
29. Tapia, V. S., Daniels, M. J. D., Palazón-Riquelme, P., Dewhurst, M., Luheshi, N. M., Rivers-Auty, J., Green, J., Redondo-Castro, E., Kaldis, P., Lopez-Castejon, G., and Brough, D. (2019) The three cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes. Journal of Biological Chemistry 294, 8325-8335
30. He, Y., Zeng, M. Y., Yang, D., Motro, B., and Nunez, G. (2016) NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354-357
31. Shi, H., Wang, Y., Li, X., Zhan, X., Tang, M., Fina, M., Su, L., Pratt, D., Bu, C. H., Hildebrand, S., Lyon, S., Scott, L., Quan, J., Sun, Q., Russell, J., Arnett, S., Jurek, P., Chen, D., Kravchenko, V. V., Mathison, J. C., Moresco, E. M., Monson, N. L., Ulevitch, R. J., and Beutler, B. (2016) NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol 17, 250-258
32. Schmid-Burgk, J. L., Chauhan, D., Schmidt, T., Ebert, T. S., Reinhardt, J., Endl, E., and Hornung, V. (2016) A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation. Journal of Biological Chemistry 291, 103-109
33. Sharif, H., Wang, L., Wang, W. L., Magupalli, V. G., Andreeva, L., Qiao, Q., Hauenstein, A. V., Wu, Z., Núñez, G., Mao, Y., and Wu, H. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome.
34. Chen, J., and Chen, Z. J. (2018) PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature 564, 71-76
35. Zhou, R., Yazdi, A. S., Menu, P., and Tschopp, J. (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221-225
36. Gross, C. J., Mishra, R., Schneider, K. S., Medard, G., Wettmarshausen, J., Dittlein, D. C., Shi, H., Gorka, O., Koenig, P. A., Fromm, S., Magnani, G., Cikovic, T., Hartjes, L., Smollich, J., Robertson, A. A. B., Cooper, M. A., Schmidt-Supprian, M., Schuster, M., Schroder, K., Broz, P., Traidl-Hoffmann, C., Beutler, B., Kuster, B., Ruland, J., Schneider, S., Perocchi, F., and Gross, O. (2016) K(+) Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria. Immunity 45, 761-773
37. Iyer, S. S., He, Q., Janczy, J. R., Elliott, E. I., Zhong, Z., Olivier, A. K., Sadler, J. J., Knepper-Adrian, V., Han, R., Qiao, L., Eisenbarth, S. C., Nauseef, W. M., Cassel, S. L., and Sutterwala, F. S. (2013) Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39, 311-323
38. Shimada, K., Crother, T. R., Karlin, J., Dagvadorj, J., Chiba, N., Chen, S., Ramanujan, V. K., Wolf, A. J., Vergnes, L., Ojcius, D. M., Rentsendorj, A., Vargas, M., Guerrero, C., Wang, Y., Fitzgerald, K. A., Underhill, D. M., Town, T., and Arditi, M. (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401-414
39. Zhong, Z., Liang, S., Sanchez-Lopez, E., He, F., Shalapour, S., Lin, X. J., Wong, J., Ding, S., Seki, E., Schnabl, B., Hevener, A. L., Greenberg, H. B., Kisseleva, T., and Karin, M. (2018) New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198-203
40. Subramanian, N., Natarajan, K., Clatworthy, M. R., Wang, Z., and Germain, R. N. (2013) The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153, 348-361
41. Park, S., Juliana, C., Hong, S., Datta, P., Hwang, I., Fernandes-Alnemri, T., Yu, J.-W., and Alnemri, E. S. (2013) The Mitochondrial Antiviral Protein MAVS Associates with NLRP3 and Regulates Its Inflammasome Activity. The Journal of Immunology 191, 4358-4366
42. Perregaux, D., and Gabel, C. A. (1994) Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. Journal of Biological Chemistry 269, 15195-15203
43. Surprenant, A., Rassendren, F., Kawashima, E., North, R. A., and Buell, G. (1996) The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272, 735-738
44. Munoz-Planillo, R., Kuffa, P., Martinez-Colon, G., Smith, B. L., Rajendiran, T. M., and Nunez, G. (2013) K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142-1153
45. Domingo-Fernández, R., Coll, R. C., Kearney, J., Breit, S., and O'Neill, L. A. J. (2017) The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome. Journal of Biological Chemistry 292, 12077-12087
46. Tang, T., Lang, X., Xu, C., Wang, X., Gong, T., Yang, Y., Cui, J., Bai, L., Wang, J., Jiang, W., and Zhou, R. (2017) CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nature Communications 8, 202
47. Daniels, M. J. D., Rivers-Auty, J., Schilling, T., Spencer, N. G., Watremez, W., Fasolino, V., Booth, S. J., White, C. S., Baldwin, A. G., Freeman, S., Wong, R., Latta, C., Yu, S., Jackson, J., Fischer, N., Koziel, V., Pillot, T., Bagnall, J., Allan, S. M., Paszek, P., Galea, J., Harte, M. K., Eder, C., Lawrence, C. B., and Brough, D. (2016) Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nature Communications 7, 12504
48. Green, J. P., Yu, S., Martin-Sanchez, F., Pelegrin, P., Lopez-Castejon, G., Lawrence, C. B., and Brough, D. (2018) Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. Proc Natl Acad Sci U S A 115, E9371-E9380
49. Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A., and Latz, E. (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunology 9, 847-856
50. Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A., and Tschopp, J. (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237-241
51. Duewell, P., Kono, H., Rayner, K. J., Sirois, C. M., Vladimer, G., Bauernfeind, F. G., Abela, G. S., Franchi, L., Nuñez, G., Schnurr, M., Espevik, T., Lien, E., Fitzgerald, K. A., Rock, K. L., Moore, K. J., Wright, S. D., Hornung, V., and Latz, E. (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357-1361
52. Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J., and Golenbock, D. T. (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunology 9, 857-865
53. Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A., and Kolodner, R. D. (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nature Genetics 29, 301-305
54. Aksentijevich, I., Nowak, M., Mallah, M., Chae, J. J., Watford, W. T., Hofmann, S. R., Stein, L., Russo, R., Goldsmith, D., Dent, P., Rosenberg, H. F., Austin, F., Remmers, E. F., Balow, J. E., Jr., Rosenzweig, S., Komarow, H., Shoham, N. G., Wood, G., Jones, J., Mangra, N., Carrero, H., Adams, B. S., Moore, T. L., Schikler, K., Hoffman, H., Lovell, D. J., Lipnick, R., Barron, K., O'Shea, J. J., Kastner, D. L., and Goldbach-Mansky, R. (2002) De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 46, 3340-3348
55. Aganna, E., Martinon, F., Hawkins, P. N., Ross, J. B., Swan, D. C., Booth, D. R., Lachmann, H. J., Bybee, A., Gaudet, R., Woo, P., Feighery, C., Cotter, F. E., Thome, M., Hitman, G. A., Tschopp, J., and McDermott, M. F. (2002) Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 46, 2445-2452
56. Sarrauste de Menthiere, C., Terriere, S., Pugnere, D., Ruiz, M., Demaille, J., and Touitou, I. (2003) INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res 31, 282-285
57. Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., Gelpi, E., Halle, A., Korte, M., Latz, E., and Golenbock, D. T. (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674-678
58. Yan, Y., Jiang, W., Liu, L., Wang, X., Ding, C., Tian, Z., and Zhou, R. (2015) Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160, 62-73
59. Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M., Tessari, I., Bubacco, L., and de Bernard, M. (2013) Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS One 8, e55375
60. Walsh, J. G., Muruve, D. A., and Power, C. (2014) Inflammasomes in the CNS. Nat Rev Neurosci 15, 84-97
61. Venegas, C., Kumar, S., Franklin, B. S., Dierkes, T., Brinkschulte, R., Tejera, D., Vieira-Saecker, A., Schwartz, S., Santarelli, F., Kummer, M. P., Griep, A., Gelpi, E., Beilharz, M., Riedel, D., Golenbock, D. T., Geyer, M., Walter, J., Latz, E., and Heneka, M. T. (2017) Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer's disease. Nature 552, 355-361
62. Ozaki, E., Campbell, M., and Doyle, S. L. (2015) Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J Inflamm Res 8, 15-27
63. Jesus, A. A., and Goldbach-Mansky, R. (2014) IL-1 blockade in autoinflammatory syndromes. Annu Rev Med 65, 223-244
64. Dinarello, C. A., Simon, A., and van der Meer, J. W. (2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 11, 633-652
65. Calabrese, L. H. (2002) Anakinra treatment of patients with rheumatoid arthritis. Ann Pharmacother 36, 1204-1209
66. Zahid, A., Li, B., Kombe, A. J. K., Jin, T., and Tao, J. (2019) Pharmacological Inhibitors of the NLRP3 Inflammasome. Front Immunol 10, 2538
67. Laliberte, R. E., Perregaux, D. G., Hoth, L. R., Rosner, P. J., Jordan, C. K., Peese, K. M., Eggler, J. F., Dombroski, M. A., Geoghegan, K. F., and Gabel, C. A. (2003) Glutathione s-transferase omega 1-1 is a target of cytokine release inhibitory drugs and may be responsible for their effect on interleukin-1beta posttranslational processing. J Biol Chem 278, 16567-16578
68. Dempsey, C., Rubio Araiz, A., Bryson, K. J., Finucane, O., Larkin, C., Mills, E. L., Robertson, A. A. B., Cooper, M. A., O'Neill, L. A. J., and Lynch, M. A. (2017) Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. Brain Behav Immun 61, 306-316
69. van der Heijden, T., Kritikou, E., Venema, W., van Duijn, J., van Santbrink, P. J., Slutter, B., Foks, A. C., Bot, I., and Kuiper, J. (2017) NLRP3 Inflammasome Inhibition by MCC950 Reduces Atherosclerotic Lesion Development in Apolipoprotein E-Deficient Mice-Brief Report. Arterioscler Thromb Vasc Biol 37, 1457-1461
70. Monnerat, G., Alarcon, M. L., Vasconcellos, L. R., Hochman-Mendez, C., Brasil, G., Bassani, R. A., Casis, O., Malan, D., Travassos, L. H., Sepulveda, M., Burgos, J. I., Vila-Petroff, M., Dutra, F. F., Bozza, M. T., Paiva, C. N., Carvalho, A. B., Bonomo, A., Fleischmann, B. K., de Carvalho, A. C. C., and Medei, E. (2016) Macrophage-dependent IL-1beta production induces cardiac arrhythmias in diabetic mice. Nat Commun 7, 13344
71. Zhai, Y., Meng, X., Ye, T., Xie, W., Sun, G., and Sun, X. (2018) Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice. Molecules 23
72. Perera, A. P., Fernando, R., Shinde, T., Gundamaraju, R., Southam, B., Sohal, S. S., Robertson, A. A. B., Schroder, K., Kunde, D., and Eri, R. (2018) MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Scientific Reports 8, 8618
73. Marchetti, C., Swartzwelter, B., Gamboni, F., Neff, C. P., Richter, K., Azam, T., Carta, S., Tengesdal, I., Nemkov, T., D'Alessandro, A., Henry, C., Jones, G. S., Goodrich, S. A., St Laurent, J. P., Jones, T. M., Scribner, C. L., Barrow, R. B., Altman, R. D., Skouras, D. B., Gattorno, M., Grau, V., Janciauskiene, S., Rubartelli, A., Joosten, L. A. B., and Dinarello, C. A. (2018) OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A 115, E1530-E1539
74. Toldo, S., and Abbate, A. (2018) The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol 15, 203-214
75. Huang, Y., Jiang, H., Chen, Y., Wang, X., Yang, Y., Tao, J., Deng, X., Liang, G., Zhang, H., Jiang, W., and Zhou, R. (2018) Tranilast directly targets NLRP3 to treat inflammasome-driven diseases. EMBO Mol Med 10
76. Jiang, H., He, H., Chen, Y., Huang, W., Cheng, J., Ye, J., Wang, A., Tao, J., Wang, C., Liu, Q., Jin, T., Jiang, W., Deng, X., and Zhou, R. (2017) Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med 214, 3219-3238
77. Konneh, M. (1998) Tranilast Kissei Pharmaceutical. IDrugs 1, 141-146
78. Platten, M., Ho, P. P., Youssef, S., Fontoura, P., Garren, H., Hur, E. M., Gupta, R., Lee, L. Y., Kidd, B. A., Robinson, W. H., Sobel, R. A., Selley, M. L., and Steinman, L. (2005) Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 310, 850-855
79. Wu, H. (2013) Higher-order assemblies in a new paradigm of signal transduction. Cell 153, 287-292
80. Kagan, J. C., Magupalli, V. G., and Wu, H. (2014) SMOCs: supramolecular organizing centres that control innate immunity. Nat Rev Immunol 14, 821-826
81. Lin, S. C., Lo, Y. C., and Wu, H. (2010) Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465, 885-890
82. Peisley, A., Wu, B., Yao, H., Walz, T., and Hur, S. (2013) RIG-I forms signaling-competent filaments in an ATP-dependent, ubiquitin-independent manner. Mol Cell 51, 573-583
83. Peisley, A., Wu, B., Xu, H., Chen, Z. J., and Hur, S. (2014) Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I. Nature 509, 110-114
84. Peisley, A., Lin, C., Wu, B., Orme-Johnson, M., Liu, M., Walz, T., and Hur, S. (2011) Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc Natl Acad Sci U S A 108, 21010-21015
85. Wu, B., Peisley, A., Richards, C., Yao, H., Zeng, X., Lin, C., Chu, F., Walz, T., and Hur, S. (2013) Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152, 276-289
86. Wu, B., Peisley, A., Tetrault, D., Li, Z., Egelman, E. H., Magor, K. E., Walz, T., Penczek, P. A., and Hur, S. (2014) Molecular imprinting as a signal-activation mechanism of the viral RNA sensor RIG-I. Mol Cell 55, 511-523
87. Blander, J. M. (2014) A long-awaited merger of the pathways mediating host defence and programmed cell death. Nat Rev Immunol 14, 601-618
88. Trinchieri, G. (2010) Type I interferon: friend or foe? J Exp Med 207, 2053-2063
89. Basel-Vanagaite, L., Attia, R., Yahav, M., Ferland, R. J., Anteki, L., Walsh, C. A., Olender, T., Straussberg, R., Magal, N., Taub, E., Drasinover, V., Alkelai, A., Bercovich, D., Rechavi, G., Simon, A. J., and Shohat, M. (2006) The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet 43, 203-210
90. Rogaeva, A., Galaraga, K., and Albert, P. R. (2007) The Freud-1/CC2D1A family: transcriptional regulators implicated in mental retardation. J Neurosci Res 85, 2833-2838
91. Nakamura, A., Naito, M., Tsuruo, T., and Fujita, N. (2008) Freud-1/Aki1, a novel PDK1-interacting protein, functions as a scaffold to activate the PDK1/Akt pathway in epidermal growth factor signaling. Mol Cell Biol 28, 5996-6009
92. Chang, C. H., Lai, L. C., Cheng, H. C., Chen, K. R., Syue, Y. Z., Lu, H. C., Lin, W. Y., Chen, S. H., Huang, H. S., Shiau, A. L., Lei, H. Y., Qin, J., and Ling, P. (2011) TBK1-associated protein in endolysosomes (TAPE) is an innate immune regulator modulating the TLR3 and TLR4 signaling pathways. J Biol Chem 286, 7043-7051
93. Chen, K. R., Chang, C. H., Huang, C. Y., Lin, C. Y., Lin, W. Y., Lo, Y. C., Yang, C. Y., Hsing, E. W., Chen, L. F., Shih, S. R., Shiau, A. L., Lei, H. Y., Tan, T. H., and Ling, P. (2012) TBK1-associated protein in endolysosomes (TAPE)/CC2D1A is a key regulator linking RIG-I-like receptors to antiviral immunity. J Biol Chem 287, 32216-32221
94. Burkhard, P., Stetefeld, J., and Strelkov, S. V. (2001) Coiled coils: a highly versatile protein folding motif. Trends in cell biology 11, 82-88
95. Lemmon, M. A. (2008) Membrane recognition by phospholipid-binding domains. Nature reviews. Molecular cell biology 9, 99-111
96. Ou, X. M., Lemonde, S., Jafar-Nejad, H., Bown, C. D., Goto, A., Rogaeva, A., and Albert, P. R. (2003) Freud-1: A neuronal calcium-regulated repressor of the 5-HT1A receptor gene. J Neurosci 23, 7415-7425
97. Rogaeva, A., and Albert, P. R. (2007) The mental retardation gene CC2D1A/Freud-1 encodes a long isoform that binds conserved DNA elements to repress gene transcription. Eur J Neurosci 26, 965-974
98. Usami, Y., Popov, S., Weiss, E. R., Vriesema-Magnuson, C., Calistri, A., and Gottlinger, H. G. (2012) Regulation of CHMP4/ESCRT-III function in human immunodeficiency virus type 1 budding by CC2D1A. J Virol 86, 3746-3756
99. Jaekel, R., and Klein, T. (2006) The Drosophila Notch inhibitor and tumor suppressor gene lethal (2) giant discs encodes a conserved regulator of endosomal trafficking. Developmental cell 11, 655-669
100. Drusenheimer, N., Migdal, B., Jackel, S., Tveriakhina, L., Scheider, K., Schulz, K., Groper, J., Kohrer, K., and Klein, T. (2015) 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 11, e1005749
101. Zhao, M., Li, X. D., and Chen, Z. (2010) CC2D1A, a DM14 and C2 domain protein, activates NF-kappaB through the canonical pathway. J Biol Chem 285, 24372-24380
102. Matsuda, A., Suzuki, Y., Honda, G., Muramatsu, S., Matsuzaki, O., Nagano, Y., Doi, T., Shimotohno, K., Harada, T., Nishida, E., Hayashi, H., and Sugano, S. (2003) Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene 22, 3307-3318
103. Manzini, M. C., Xiong, L., Shaheen, R., Tambunan, D. E., Di Costanzo, S., Mitisalis, V., Tischfield, D. J., Cinquino, A., Ghaziuddin, M., Christian, M., Jiang, Q., Laurent, S., Nanjiani, Z. A., Rasheed, S., Hill, R. S., Lizarraga, S. B., Gleason, D., Sabbagh, D., Salih, M. A., Alkuraya, F. S., and Walsh, C. A. (2014) CC2D1A regulates human intellectual and social function as well as NF-kappaB signaling homeostasis. Cell Rep 8, 647-655
104. Yang, C. Y., Yu, T. H., Wen, W. L., Ling, P., and Hsu, K. S. (2019) Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation. J Neurosci 39, 4959-4975
105. Luo, Y. C. (2012) Roles of an innate immune adaptor TAPE and endolysosomes in RIG-I-like receptor signaling. Master, National Cheng Kung University
106. de Souza, E. E., Meirelles, G. V., Godoy, B. B., Perez, A. M., Smetana, J. H., Doxsey, S. J., McComb, M. E., Costello, C. E., Whelan, S. A., and Kobarg, J. (2014) Characterization of the human NEK7 interactome suggests catalytic and regulatory properties distinct from those of NEK6. J Proteome Res 13, 4074-4090
107. C.C., K. (2015) Emerging roles of TAPE innate immune adaptor in inflammasome regulation and Gram-negative bacterial infection. Master, National Cheng Kung University
108. Hou, F., Sun, L., Zheng, H., Skaug, B., Jiang, Q. X., and Chen, Z. J. (2011) MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448-461
109. Yanai, H., Ban, T., Wang, Z., Choi, M. K., Kawamura, T., Negishi, H., Nakasato, M., Lu, Y., Hangai, S., Koshiba, R., Savitsky, D., Ronfani, L., Akira, S., Bianchi, M. E., Honda, K., Tamura, T., Kodama, T., and Taniguchi, T. (2009) HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462, 99-103
110. Nakamura, N., Lill, J. R., Phung, Q., Jiang, Z., Bakalarski, C., de Maziere, A., Klumperman, J., Schlatter, M., Delamarre, L., and Mellman, I. (2014) Endosomes are specialized platforms for bacterial sensing and NOD2 signalling. Nature 509, 240-244
111. Irving, A. T., Mimuro, H., Kufer, T. A., Lo, C., Wheeler, R., Turner, L. J., Thomas, B. J., Malosse, C., Gantier, M. P., Casillas, L. N., Votta, B. J., Bertin, J., Boneca, I. G., Sasakawa, C., Philpott, D. J., Ferrero, R. L., and Kaparakis-Liaskos, M. (2014) The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. Cell Host Microbe 15, 623-635
112. J.B., C. (2019) Molecular mechanism of TAPE in regulation of RIG-I activation. Master, National Cheng Kung University