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研究生: 洪禎憶
Hong, Jhen-Yi
論文名稱: 利用生化與分子結構研究參與NF-κB訊息傳遞路徑之重要調節蛋白
Utilizing structural and biochemical tools to dissect the interplay between the key mediators in NF-κB signaling pathway
指導教授: 羅玉枝
Lo, Yu-Chiu
學位類別: 博士
Doctor
系所名稱: 生物科學與科技學院 - 生物科技與產業科學系
Department of Biotechnology and Bioindustry Sciences
論文出版年: 2021
畢業學年度: 109
語文別: 英文
論文頁數: 178
中文關鍵詞: 線性泛素鏈
外文關鍵詞: Abin1, A20, NEMO, linear poly-ubiquitin, TRAF6
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  • Chinese Abstract (中文摘要 ) I Abstract II Acknowledgements VI Table of Contents VII Contents of Tables XI Contents of Figures XII Contents of Appendices XVII Abbreviation List XVIII 1. Research Background 1 1-1 The NF-κB signaling pathway 1 1-2 The IKK complex 2 1-3 The TNF-receptor-associated factor 6 (TRAF6) 5 1-4 Ubiquitination and its role for activation of NF-κB 6 1-5 Inactivation of NF-κB by deubiquitinase 8 1-6 Introduction of ABIN1 9 1-7 The current structure of UBAN proteins and poly-ubiquitin complex 11 1-8 The aim of this study 12 2. Materials and Methods 15 2-1 Cloning, proteins expression and purification 15 2-2 Crystallization and structure determination 16 2-3 His-tag pull-down Assay 17 2-4 Isothermal titration calorimetry (ITC) and data analysis 18 2-5 Multi-Angle Light Scattering (MALS) analyses 19 3. Results 20 3-1 An investigation of interaction with NEMO N-terminus and TRAF6 coiled-coil domain shown they could not form a complex 20 3-2 The IKKβ:IκBα protein complexes were successfully purified by size-exclusion chromatography 21 3-3 The NEMO zinc-finger domain is not responsible for interacting with IκBα or K63-linked poly-Ub and the purification conditions of NEMO-ZnF protein was optimized 23 3-4 Overall structure of hABIN1-UBAN in complex with tandem poly-Ub demonstrate a molecular stoichiometric ratio is 2:1 of hABIN1 to poly-Ub 25 3-5 The structural comparison of the concave or convex site of the linear di-Ub in each hABIN1:polyUb structures demonstrates the linear di-Ub is flexible 26 3-6 The structural comparison of UBAN proteins in complex with linear poly-Ub demonstrate the di-Ub is basic binding unit for UBAN domain 27 3-7 The detail interfaces between hABIN1-UBAN and tandem di-Ub demonstrate first Ub utilizes Ile36, Ile44 patches to interact with UBAN domain whereas second Ub mediate the binding with UBAN domain through Phe4 and TEK-box 29 3-8 The structural-based site-directed mutagenesis confirmed the interfaces between hABIN1-UBAN and di, tri-Ub are identical with crystal structure and the recognition sites are near Met-1 residue 31 3-9 The structural-based site-directed mutagenesis on hABIN1-UBAN demonstrate the diseasing-causing mutation lead to severely disruption of the interface between UBAN domain and linear poly-Ub 32 3-10 The different binding affinity between linear and K63-linked poly-Ub is caused by Met-1 linkage and following secondary structure restrain the orientation of second Ub and the binding mode between linear and K63-linked poly-Ub are similar 34 3-11 The phosphorylation on hABIN1-UBAN enhance the binding affinity with K63-linked poly-Ub in this study 35 3-12 Longer linear poly-Ub enhance their binding affinity and aggregation of hABIN1 36 3-13 Long linear poly-Ub plays as a platform to recruit UBAN proteins that mediate TNF-mediated signaling pathway 38 3-14 The purification conditions of ABIN1-UBAN in complex with linear poly-Ub was optimized in this study 40 3-15 The purification conditions of NEMO-UBAN in complex with linear poly-Ub was optimized in this study 42 3-16 The purification conditions of NEMO CC2-LZ-ZnF in complex with linear poly-Ub was optimized in this study 44 3-17 The pull-down assay demonstrated ABIN1 utilizes its AHD domain to interact with A20 ZnF2 to ZnF3 domain whereas ABIN1-NBD could not interact with NEMO N-terminus in this study 45 4. Discussion 47 References 57 Tables 69 Figures 85 Appendices 163

    Adams, P. D., Grosse-Kunstleve, R. W., Hung, L. W., Ioerger, T. R., McCoy, A. J., Moriarty, N. W., Read, R. J., Sacchettini, J. C., Sauter, N. K. and Terwilliger, T. C. PHENIX: building new software for automated crystallographic structure determination. Acta Crystallographica Section D-Structural Biology 58, 1948-1954, 2002.
    Arch, R. H., Gedrich, R. W. and Thompson, C. B. Tumor necrosis factor receptor-associated factors (TRAFs)-a family of adapter proteins that regulates life and death. Genes and Development 12, 2821-2830,1998.
    Bagneris, C., Ageichik, A.V., Cronin, N., Wallace, B., Collins, M., Boshoff, C., Waksman, G. and Barrett, T. Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. Molecular Cell 30, 620-631, 2008.
    Baltimore, D. Discovering NF-kappaB. Cold Spring Harbor Perspectives in Biology 1, a000026, 2009.
    Bavikar, S. N., Spasser, L., Haj-Yahya, M., Karthikeyan, S. V., Moyal, T., Kumar, K. S. and Brik, A. (2012). Chemical synthesis of ubiquitinated peptides with varying lengths and types of ubiquitin chains to explore the activity of deubiquitinases. Angewandte Chemie-International Edition 51, 758-763.
    Bosanac, I., Wertz, I.E., Pan, B., Yu, C., Kusam, S., Lam, C., Phu, L., Phung, Q., Maurer, B., Arnott, D., Kirkpatrick, D.S., Dixit, V.M. and Hymowitz, S.G. Ubiquitin binding to A20 ZnF4 is required for modulation of NF-kappaB signaling. Molecular Cell 40, 548-557, 2010.
    Brikos, C., Wait, R., Begum, S., O'Neill, L.A. and Saklatvala, J. Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components. Molecular Cell Proteomics 6, 1551-1559, 2007.
    Cai, J., Hu, D., Sakya, J., Sun, T., Wang, D., Wang, L., Mao, X. and Su, Z. ABIN-1 is a key regulator in RIPK1-dependent apoptosis (RDA) and necroptosis, and ABIN-1 deficiency potentiates necroptosis-based cancer therapy in colorectal cancer. Cell Death and Disease 12, 140, 2021.
    Callahan, J.A., Hammer, G.E., Agelides, A., Duong, B.H., Oshima, S., North, J., Advincula, R., Shifrin, N., Truong, H.A., Paw, J., Barrera, J., DeFranco, A., Rosenblum, M.D., Malynn, B.A. and Ma, A. Cutting edge: ABIN-1 protects against psoriasis by restricting MyD88 signals in dendritic cells. Journal of Immunology 191, 535-539, 2013.
    Cao, Z., Xiong, J., Takeuchi, M., Kurama, T. and Goeddel, D. V. TRAF6 is a signal transducer for interleukin-1. Nature 383, 443-446, 1996.
    Caster, D.J., Korte, E.A., Nanda, S.K., McLeish, K.R., Oliver, R.K., G'Sell R, T., Sheehan, R.M., Freeman, D.W., Coventry, S.C., Kelly, J.A., Guthridge, J.M., James, J.A., Sivils, K.L., Alarcon-Riquelme, M.E., Scofield, R.H., Adrianto, I., Gaffney, P.M., Stevens, A.M., Freedman, B.I., Langefeld, C.D., Tsao, B.P., Pons-Estel, B.A., Jacob, C.O., Kamen, D.L., Gilkeson, G.S., Brown, E.E., Alarcon, G.S., Edberg, J.C., Kimberly, R.P., Martin, J., Merrill, J.T., Harley, J.B., Kaufman, K.M., Reveille, J.D., Anaya, J.M., Criswell, L.A., Vila, L.M., Petri, M., Ramsey-Goldman, R., Bae, S.C., Boackle, S.A., Vyse, T.J., Niewold, T.B., Cohen, P. and Powell, D.W. ABIN1 dysfunction as a genetic basis for lupus nephritis. Journal of the American Society of Nephrology 24, 1743-1754, 2013.
    Catici, D.A., Horne, J.E., Cooper, G.E. and Pudney, C.R. Polyubiquitin Drives the Molecular Interactions of the NF-kappaB Essential Modulator (NEMO) by Allosteric Regulation. The Journal of Biological Chemistry 290, 14130-14139, 2015.
    Cordier, F., Vinolo, E., Veron, M., Delepierre, M. and Agou, F. Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation. Journal of Molecular Biology 377, 1419-1432, 2008.
    Cordier, F., Grubisha, O., Traincard, F., Veron, M., Delepierre, M. and Agou, F. The zinc finger of NEMO is a functional ubiquitin-binding domain. The Journal of Biological Chemistry 284, 2902-2907, 2009.
    Courtois, G. and Gilmore, T.D. Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene 25, 6831-6843, 2006.
    Dhillon, B., Aleithan, F., Abdul-Sater, Z. and Abdul-Sater, A.A. The Evolving Role of TRAFs in Mediating Inflammatory Responses. Frontiers in Immunology 10, 104, 2019.
    Dikic, I., Wakatsuki, S. and Walters, K.J. Ubiquitin-binding domains-from structures tofunctions. Nature Review Molecular Cell Biology 10, 659-671, 2009.
    Döffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., Headon, D. J., Overbeek, P. A., Le Deist, F., Holland, S. M., Belani, K., Kumararatne, D. S., Fischer, A., Shapiro, R., Conley, M. E., Reimund, E., Kalhoff, H., Abinun, M., Munnich, A., Israël, A., Courtois, G. and Casanova, J. L. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nature Genetics 27, 277-285, 2001.
    Dong, G., Chanudet, E., Zeng, N., Appert, A., Chen, Y.W., Au, W.Y., Hamoudi, R.A., Watkins, A.J., Ye, H., Liu, H., Gao, Z., Chuang, S.S., Srivastava, G. and Du, M.Q. A20, ABIN-1/2, and CARD11 mutations and their prognostic value in gastrointestinal diffuse large B-cell lymphoma. Clinical Cancer Research 17, 1440-1451, 2011.
    Dziedzic, S.A., Su, Z., Jean Barrett, V., Najafov, A., Mookhtiar, A.K., Amin, P., Pan, H., Sun, L., Zhu, H., Ma, A., Abbott, D.W. and Yuan, J. ABIN-1 regulates RIPK1 activation by linking Met1 ubiquitylation with Lys63 deubiquitylation in TNF-RSC. Nature Cell Biology 20, 58-68, 2018.
    Emsley, P. and Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallographica Section D-Structural Biology 60, 2126-2132, 2004.
    Gao, L., Coope, H., Grant, S., Ma, A., Ley, S.C. and Harhaj, E.W. ABIN1 protein cooperates with TAX1BP1 and A20 proteins to inhibit antiviral signaling. The Journal of Biological Chemistry 286, 36592-36602, 2011.
    Gautheron, J., Pescatore, A., Fusco, F., Esposito, E., Yamaoka, S., Agou, F., Ursini, M.V. and Courtois, G. Identification of a new NEMO/TRAF6 interface affected in incontinentia pigmenti pathology. Human Molecular Genetics 19, 3138-3149, 2010.
    Ghosh, S., May, M. J. and Kopp, E. B. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology 16, 225-260, 1998.
    G'Sell, R.T., Gaffney, P.M. and Powell, D.W. A20-Binding Inhibitor of NF-kappaB Activation 1 is a Physiologic Inhibitor of NF-kappaB: A Molecular Switch for Inflammation and Autoimmunity. Arthritis and Rheumatology 67, 2292-2302, 2015.
    Haas, T. L., Emmerich, C. H., Gerlach, B., Schmukle, A. C., Cordier, S. M., Rieser, E., Feltham, R., Vince, J., Warnken, U., Wenger, T., Koschny, R., Komander, D., Silke, J. and Walczak, H. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Molecular Cell 36, 831-844, 2009.
    Hauenstein, A.V., Xu, G., Kabaleeswaran, V. and Wu, H. Evidence for M1-Linked Polyubiquitin-Mediated Conformational Change in NEMO. Journal of Molecular Biology 429, 3793-3800, 2017.
    Hayden, M. S. and Ghosh, S. Signaling to NF-kappaB. Genes and Development 18, 2195-2224, 2004.
    Herhaus, L., van den Bedem, H., Tang, S., Maslennikov, I., Wakatsuki, S., Dikic, I. and Rahighi, S. Molecular Recognition of M1-Linked Ubiquitin Chains by Native and Phosphorylated UBAN Domains. Journal of Molecular Biology 431, 3146-3156, 2019.
    Heyninck, K., De Valck, D., Vanden Berghe, W., Van Criekinge, W., Contreras, R., Fiers, W., Haegeman, G. and Beyaert, R. The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN. The Journal of Cell Biology 145, 1471-1482, 1999.
    Heyninck, K., Kreike, M. M. and Beyaert, R. Structure-function analysis of the A20-binding inhibitor of NF-kappa B activation, ABIN-1. Federation of European Biochemical Societies 536, 135-140, 2003.
    Hsu, H., Huang, J., Shu, H.B., Baichwal, V. and Goeddel, D.V. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4, 387-396, 1996.
    Hu, L., Xu, J., Xie, X., Zhou, Y., Tao, P., Li, H., Han, X., Wang, C., Liu, J., Xu, P., Neculai, D. and Xia, Z. Oligomerization-primed coiled-coil domain interaction with Ubc13 confers processivity to TRAF6 ubiquitin ligase activity. Nature Communication 8, 814, 2017.
    Huang, T.T., Feinberg, S.L., Suryanarayanan, S. and Miyamoto, S. The zinc finger domain of NEMO is selectively required for NF-kappa B activation by UV radiation and topoisomerase inhibitors. Molecular Cell Biology 22, 5813-5825, 2002.
    Huang, X. A Time-Efficient, Linear-Space Local Similarity Algorithm. Advances In Applied Mathematics 12, 337-357, 1991.
    Hubeau, M., Ngadjeua, F., Puel, A., Israel, L., Feinberg, J., Chrabieh, M., Belani, K., Bodemer, C., Fabre, I., Plebani, A., Boisson-Dupuis, S., Picard, C., Fischer, A., Israel, A., Abel, L., Veron, M., Casanova, J.L., Agou, F. and Bustamante, J. New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein. Blood 118, 926-935, 2011.
    Hurley, J. H., Lee, S. and Prag, G. Ubiquitin-binding domains. The Biochemical Journal 399, 361-372, 2006.
    Israël A. The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harbor Perspectives in Biology 2, a000158, 2010.
    Ivins, F.J., Montgomery, M.G., Smith, S.J., Morris-Davies, A.C., Taylor, I.A. and Rittinger, K. NEMO oligomerization and its ubiquitin-binding properties. The Biochemical Journal 421, 243-251, 2009.
    Iwai, K. Diverse ubiquitin signaling in NF-kappaB activation. Trends in Cell Biology 22, 355-364, 2012.
    Jussupow, A., Messias, A. C., Stehle, R., Geerlof, A., Solbak, S., Paissoni, C., Bach, A., Sattler, M. and Camilloni, C. The dynamics of linear polyubiquitin. Science Advances 6, eabc3786, 2020.
    Karin, M. How NF-kB is activated: the role of the IkB kinase (IKK) complex. Oncogene 18, 6867-6874, 1999.
    Keusekotten, K., Elliott, P. R., Glockner, L., Fiil, B. K., Damgaard, R. B., Kulathu, Y., Wauer, T., Hospenthal, M. K., Gyrd-Hansen, M., Krappmann, D., Hofmann, K. and Komander, D. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 153, 1312-1326, 2013.
    Kirisako, T., Kamei, K., Murata, S., Kato, M., Fukumoto, H., Kanie, M., Sano, S., Tokunaga,F., Tanaka, K. and Iwai, K. A ubiquitin ligase complex assembles linear polyubiquitin chains. European Molecular Biology Organization 25, 4877-4887, 2006.
    Komander, D. and Rape, M. The ubiquitin code. Annual Review of Biochemistry 81, 203-229, 2012.
    Komander, D., Reyes-Turcu, F., Licchesi, J. D., Odenwaelder, P., Wilkinson, K. D. and Barford, D. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. European Molecular Biology Organization 10, 466-473, 2009.
    Kulathu, Y. and Komander, D. Atypical ubiquitylation-the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nature Reviews Molecular Cell Biology 13, 508-523, 2012.
    Krissinel, E. and Henrick, K. Inference of macromolecular assemblies from crystalline state. Journal of Molecular Biology 372, 774-797, 2007.
    Lamothe, B., Besse, A., Campos, A. D., Webster, W. K., Wu, H. and Darnay, B. G. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation. The Journal of Biological Chemistry 282, 4102-4112, 2007.
    Laplantine, E., Fontan, E., Chiaravalli, J., Lopez, T., Lakisic, G., Veron, M., Agou, F. and Israel, A. NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain. European Molecular Biology Organization 28, 2885-2895, 2009.
    Laskowski, R.A., Jablonska, J., Pravda, L., Varekova, R.S. and Thornton, J.M. PDBsum: Structural summaries of PDB entries. Protein Society 27, 129-134, 2018.
    Li, F., Xu, D., Wang, Y., Zhou, Z., Liu, J., Hu, S., Gong, Y., Yuan, J. and Pan, L. Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation. Autophagy 14, 66-79, 2018.
    Li, S., Strelow, A., Fontana, E.J. and Wesche, H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proceedings of the National Academy of Sciences of the United States of America 99, 5567-5572, 2002.
    Lin, S.M., Lin, S.C., Hong, J.Y., Su, T.W., Kuo, B.J., Chang, W.H., Tu, Y.F. and Lo, Y.C. Structural Insights into Linear Tri-ubiquitin Recognition by A20-Binding Inhibitor of NF-kappaB, ABIN-2. Structure 25, 66-78, 2017.
    Liu, F., Xia, Y., Parker, A. S. and Verma, I. M. IKK biology. Immunological Reviews 246, 239-253, 2012.
    Liu, S., Misquitta, Y.R., Olland, A., Johnson, M.A., Kelleher, K.S., Kriz, R., Lin, L.L., Stahl, M. and Mosyak, L. Crystal structure of a human IkappaB kinase beta asymmetric dimer. Journal of Biological Chemistry 288, 22758-22767, 2013.
    Lo, Y.C., Lin, S.C., Rospigliosi, C.C., Conze, D.B., Wu, C.J., Ashwell, J.D., Eliezer, D. and Wu, H. Structural basis for recognition of diubiquitins by NEMO. Molecular Cell 33, 602-615, 2009.
    Lutz, J., Höllmüller, E., Scheffner, M., Marx, A. and Stengel, F. The Length of a Ubiquitin Chain: A General Factor for Selective Recognition by Ubiquitin-Binding Proteins. Angewandte Chemie-International Edition 59, 12371-12375, 2020.
    Makris, C., Roberts, J.L. and Karin, M. The carboxyl-terminal region of IkappaB kinase gamma (IKKgamma) is required for full IKK activation. Molecular Cell Biology 22, 6573-6581, 2002.
    Mauro, C., Pacifico, F., Lavorgna, A., Mellone, S., Iannetti, A., Acquaviva, R., Formisano, S., Vito, P. and Leonardi, A. ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. Journal of Biological Chemistry 281, 18482-18488, 2006.
    McDonnell, A.V., Jiang, T., Keating, A.E. and Berger, B. Paircoil2: improved prediction of coiled coils from sequence. Bioinformatics 22, 356-358, 2006.
    Minegishi, Y., Nakayama, M., Iejima, D., Kawase, K. and Iwata, T. Significance of optineurin mutations in glaucoma and other diseases. Progress in Retinal and Eye Research 55, 149-181, 2016.
    Nakazawa, S., Oikawa, D., Ishii, R., Ayaki, T., Takahashi, H., Takeda, H., Ishitani, R., Kamei, K., Takeyoshi, I., Kawakami, H., Iwai, K., Hatada, I., Sawasaki, T., Ito, H., Nureki, O. and Tokunaga, F. Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis. Nature Communication 7, 12547, 2016.
    Nanda, S.K., Venigalla, R.K., Ordureau, A., Patterson-Kane, J.C., Powell, D.W., Toth, R., Arthur, J.S. and Cohen, P. Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. The Journal of Experimental Medicine 208, 1215-1228, 2011.
    Ngadjeua, F., Chiaravalli, J., Traincard, F., Raynal, B., Fontan, E. and Agou, F. Two-sided ubiquitin binding of NF-kappaB essential modulator (NEMO) zinc finger unveiled by a mutation associated with anhidrotic ectodermal dysplasia with immunodeficiency syndrome. Journal of Biological Chemistry 288, 33722-33737, 2013.
    Oeckinghaus, A. and Ghosh, S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harbor Perspectives in Biology 1, a000034, 2009.
    Oshima, S., Turer, E. E., Callahan, J. A., Chai, S., Advincula, R., Barrera, J., Shifrin, N., Lee, B., Benedict Yen, T. S., Woo, T., Malynn, B. A. and Ma, A. ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature 457, 906-909, 2009.
    Otwinowski, Z. and Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods in Enzymology 276, 307-326, 1997.
    Palkowitsch, L., Leidner, J., Ghosh, S. and Marienfeld, R. B. Phosphorylation of serine 68 in the IkappaB kinase (IKK)-binding domain of NEMO interferes with the structure of the IKK complex and tumor necrosis factor-alpha-induced NF-kappaB activity. The Journal of Biological Chemistry 283, 76-86, 2008.
    Pickart, C.M. and Eddins, M.J. Ubiquitin: structures, functions, mechanisms. Biochimica et Biophysica Acta-Molecular Cell Research 1695, 55-72, 2004.
    Polley, S., Huang, D.B., Hauenstein, A.V., Fusco, A.J., Zhong, X., Vu, D., Schrofelbauer, B., Kim, Y., Hoffmann, A., Verma, I.M., Ghosh, G. and Huxford, T. A structural basis for IkappaB kinase 2 activation via oligomerization-dependent trans auto-phosphorylation. PLoS Biology 11, e1001581, 2013.
    Polley, S., Passos, D.O., Huang, D.B., Mulero, M.C., Mazumder, A., Biswas, T., Verma, I.M., Lyumkis, D. and Ghosh, G. Structural Basis for the Activation of IKK1/alpha. Cell Reports 17, 1907-1914, 2016.
    Rahighi, S., Ikeda, F., Kawasaki, M., Akutsu, M., Suzuki, N., Kato, R., Kensche, T., Uejima, T., Bloor, S., Komander, D., Randow, F., Wakatsuki, S. and Dikic, I. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell 136, 1098-1109, 2009.
    Rittinger, K. and Ikeda, F. Linear ubiquitin chains: enzymes, mechanisms and biology. Open Biology 7, 170026, 2017.
    Rivkin, E., Almeida, S. M., Ceccarelli, D. F., Juang, Y. C., MacLean, T. A., Srikumar, T., Huang, H., Dunham, W. H., Fukumura, R., Xie, G., Gondo, Y., Raught, B., Gingras, A. C., Sicheri, F. and Cordes, S. P. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature 498, 318-324, 2013.
    Rothwarf, D. M., Zandi, E., Natoli, G. and Karin, M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395, 297-300, 1998.
    Rushe, M., Silvian, L., Bixler, S., Chen, L.L., Cheung, A., Bowes, S., Cuervo, H., Berkowitz, S., Zheng, T., Guckian, K., Pellegrini, M. and Lugovskoy, A. Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure 16, 798-808, 2008.
    Sato, Y., Fujita, H., Yoshikawa, A., Yamashita, M., Yamagata, A., Kaiser, S. E., Iwai, K. and Fukai, S. Specific recognition of linear ubiquitin chains by the Npl4 zinc finger (NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex. Proceedings of the National Academy of Sciences of the United States of America 108, 20520-20525, 2011.
    Schindelin, J., Rueden, C.T., Hiner, M.C. and Eliceiri, K.W. The ImageJ ecosystem: An open platform for biomedical image analysis. Molecular Reproduction and Development 82, 518-529, 2015.
    Scholefield, J., Henriques, R., Savulescu, A.F., Fontan, E., Boucharlat, A., Laplantine, E., Smahi, A., Israel, A., Agou, F. and Mhlanga, M.M. Super-resolution microscopy reveals a preformed NEMO lattice structure that is collapsed in incontinentia pigmenti. Nature Communication 7, 12629, 2016.
    Schrofelbauer, B., Polley, S., Behar, M., Ghosh, G. and Hoffmann, A. NEMO ensures signaling specificity of the pleiotropic IKKbeta by directing its kinase activity toward IkappaBalpha. Molecular Cell 47, 111-121, 2012.
    Sebban-Benin, H., Pescatore, A., Fusco, F., Pascuale, V., Gautheron, J., Yamaoka, S., Moncla, A., Ursini, M. V. and Courtois, G. Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti. Human Molecular Genetics 16, 2805-2815, 2007.
    Shabek, N., Herman-Bachinsky, Y., Buchsbaum, S., Lewinson, O., Haj-Yahya, M., Hejjaoui, M., Lashuel, H. A., Sommer, T., Brik, A. and Ciechanover, A. The size of the proteasomal substrate determines whether its degradation will be mediated by mono- or polyubiquitylation. Molecular Cell 48, 87-97, 2012.
    Shimizu, S., Fujita, H., Sasaki, Y., Tsuruyama, T., Fukuda, K. and Iwai, K. Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection. Molecular and Cellular Biology 36, 1569-1583, 2016.
    Shu, H. B., Takeuchi, M. and Goeddel, D. V. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proceedings of the National Academy of Sciences of the United States of America 93, 13973-13978, 1996.
    Singh, S. K., Sahu, I., Mali, S. M., Hemantha, H. P., Kleifeld, O., Glickman, M. H. and Brik, A. Synthetic Uncleavable Ubiquitinated Proteins Dissect Proteasome Deubiquitination and Degradation, and Highlight Distinctive Fate of Tetraubiquitin. Journal of the American Chemical Society 138, 16004-16015, 2016.
    Sun, S.C. Non-canonical NF-kappaB signaling pathway. Cell Research 21, 71-85, 2011.
    Sun, H., Mali, S. M., Singh, S. K., Meledin, R., Brik, A., Kwon, Y. T., Kravtsova-Ivantsiv, Y., Bercovich, B. and Ciechanover, A. Diverse fate of ubiquitin chain moieties: The proximal is degraded with the target, and the distal protects the proximal from removal and recycles. Proceedings of the National Academy of Sciences of the United States of America 116, 7805-7812, 2019.
    Reyes-Turcu, F. E., Shanks, J. R., Komander, D. and Wilkinson, K. D. Recognition of polyubiquitin isoforms by the multiple ubiquitin binding modules of isopeptidase T. The Journal of Biological Chemistry 283, 19581-19592, 2008.
    Thrower, J. S., Hoffman, L., Rechsteiner, M. and Pickart, C. M. Recognition of the polyubiquitin proteolytic signal. European Molecular Biology Organization 19, 94-102, 2000.
    Tokunaga, F., Nishimasu, H., Ishitani, R., Goto, E., Noguchi, T., Mio, K., Kamei, K., Ma, A., Iwai, K. and Nureki, O. Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-kappaB regulation. European Molecular Biology Organization 31, 3856-3870, 2012.
    Tokunaga, F., Sakata, S., Saeki, Y., Satomi, Y., Kirisako, T., Kamei, K., Nakagawa, T., Kato, M., Murata, S., Yamaoka, S., Yamamoto, M., Akira, S., Takao, T., Tanaka, K. and Iwai, K. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nature Cell Biology 11, 123-132, 2009.
    Tokunaga, F. and Iwai, K. Linear ubiquitination: a novel NF-κB regulatory mechanism for inflammatory and immune responses by the LUBAC ubiquitin ligase complex. Endocrine Journal 59, 641-652, 2012.
    Tsuchiya, H., Burana, D., Ohtake, F., Arai, N., Kaiho, A., Komada, M., Tanaka, K. and Saeki, Y. Ub-ProT reveals global length and composition of protein ubiquitylation in cells. Nature Communications 9, 524, 2018.
    Vince, J.E., Pantaki, D., Feltham, R., Mace, P.D., Cordier, S.M., Schmukle, A.C., Davidson, A.J., Callus, B.A., Wong, W.W., Gentle, I.E., Carter, H., Lee, E.F., Walczak, H., Day, C.L., Vaux, D.L. and Silke, J. TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (TNF) to efficiently activate NF-kappaB and to prevent tnf-induced apoptosis. Journal of Biological Chemistry 284, 35906-35915, 2009.
    Vincendeau, M., Hadian, K., Messias, A.C., Brenke, J.K., Halander, J., Griesbach, R., Greczmiel, U., Bertossi, A., Stehle, R., Nagel, D., Demski, K., Velvarska, H., Niessing, D., Geerlof, A., Sattler, M. and Krappmann, D. Inhibition of Canonical NF-kappaB Signaling by a Small Molecule Targeting NEMO-Ubiquitin Interaction. Scientific Reports 6, 18934, 2016.
    Vijay-Kumar, S., Bugg, C. E. and Cook, W. J. Structure of ubiquitin refined at 1.8 A resolution. Journal of Molecular Biology 194, 531-544, 1987.
    Wagner, S., Carpentier, I., Rogov, V., Kreike, M., Ikeda, F., Lohr, F., Wu, C.J., Ashwell, J.D., Dotsch, V., Dikic, I. and Beyaert, R. Ubiquitin binding mediates the NF-kappaB inhibitory potential of ABIN proteins. Oncogene 27, 3739-3745, 2008.
    Wertz, I. E., O'Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., Wu, P., Wiesmann, C., Baker, R., Boone, D. L., Ma, A., Koonin, E. V. and Dixit, V. M. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430, 694-699,2004.
    Wullaert, A., Verstrepen, L., Van Huffel, S., Adib-Conquy, M., Cornelis, S., Kreike, M., Haegman, M., El Bakkouri, K., Sanders, M., Verhelst, K., Carpentier, I., Cavaillon, J.-M., Heyninck, K. and Beyaert, R. LIND/ABIN-3 Is a Novel Lipopolysaccharide-inducible Inhibitor of NF-κB Activation. Journal of Biological Chemistry 282, 81-90, 2007.
    Wu, Y., He, X., Huang, N., Yu, J. and Shao, B. A20: a master regulator of arthritis. Arthritis Research and Therapy 22, 220, 2020.
    Xu, G., Lo, Y.C., Li, Q., Napolitano, G., Wu, X., Jiang, X., Dreano, M., Karin, M. and Wu, H. Crystal structure of inhibitor of kappaB kinase beta. Nature 472, 325-330, 2011.
    Yin, Q., Lin, S.C., Lamothe, B., Lu, M., Lo, Y.C., Hura, G., Zheng, L., Rich, R.L., Campos, A.D., Myszka, D.G., Lenardo, M.J., Darnay, B.G. and Wu, H. E2 interaction and dimerization in the crystal structure of TRAF6. Nature Structure and Molecular Biology 16, 658-666, 2009.
    Yoshikawa, A., Sato, Y., Yamashita, M., Mimura, H., Yamagata, A. and Fukai, S. Crystal structure of the NEMO ubiquitin-binding domain in complex with Lys 63-linked di-ubiquitin. Federation of European Biochemical Societies 583, 3317-3322, 2009.

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