リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「炎症刺激時における炎症関連RNA分解酵素Regnase-1の制御機構の解析」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

炎症刺激時における炎症関連RNA分解酵素Regnase-1の制御機構の解析

赤木, 宏太朗 京都大学 DOI:10.14989/doctor.k24048

2022.03.23

概要

RNA分解酵素であるRegnase-1は、Interleukin(IL)-6などの炎症関連分子をコードするmRNAを分解することにより、過剰な炎症が起きるのを防ぐ役割を担うと考えられている。一方、IL-1bやLipopolysaccharide(LPS)などの炎症刺激下において、Regnase-1自体のタンパク質発現がどのような制御を受けるかについては不明な点が残されていた。申請者はRegnase-1結合タンパク質の網羅的な解析を行い、IL-1b刺激依存的なRegnase-1の結合パートナーとして14-3-3タンパク質を同定した。14-3-3はリン酸化タンパク質に結合することが知られており、IL-1b刺激によりRegnase-1のアミノ酸配列における494番目と513番目の2つのセリン残基(S494、S513)がリン酸化を受けることにより、14-3-3と結合することが分かった。また、Regnase-1と14-3-3の結合はIL-1bだけでなく、LPSなどのToll-likereceptorリガンド刺激によっても誘導された。Regnase-1と14-3-3の結合を誘導するこれらの刺激の細胞内シグナル伝達は、アダプタータンパク質MyD88に依存しており、その下流で活性化するIL-1receptor-associatedkinase1のC末端構造ドメインがRegnase-1と14-3-3の複合体形成に必須であることが分かった。MyD88依存性の刺激下においては、Regnase-1がb-transducin repeat containing protein(bTRCP)と結合し、ユビキチン化を介したタンパク質分解を受けることが知られているが、14-3-3はbTRCPとRegnase-1の結合を阻害し、Regnase-1のタンパク質安定化に寄与している可能性が示唆された。実際に、Regnase-1が14-3-3と結合できないような変異(Regnase-1S513A/S513A変異)を持つノックインマウスを作製し、そのマウス由来の細胞を解析したところ、変異Regnase-1はMyD88依存性の刺激下でタンパク質として不安定であることが分かった。その一方で、14-3-3と結合しタンパク質として安定なRegnase-1は分解標的mRNAと結合することができず、Regnase-1のRNA分解酵素としての機能が抑制されることが、RNA免疫沈降などの解析により明らかとなった。さらに、14-3-3と結合していないRegnase-1が細胞内で核と細胞質をシャトルする性質を持つのに対し、14-3-3と結合したRegnase-1は核への移行ができなくなっていることが分かった。以上の解析結果から、MyD88依存性の刺激下では、14-3-3がRegnase-1を細胞質にとどめ、Regnase-1の機能を抑制することにより、炎症関連遺伝子が適切に発現するように調節していると結論づけた。

参考文献

Afgan, E., Baker, D., Batut, B., Van Den Beek, M., Bouvier, D., Ech, M., Chilton, J., Clements,D., Coraor, N., Grüning, B. A., Guerler, A., Hillman-Jackson, J., Hiltemann, S., Jalili, V., Rasche, H., Soranzo, N., Goecks, J., Taylor, J., Nekrutenko, A., & Blankenberg, D. (2018). The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update. Nucleic Acids Research, 46(W1), W537–W544. https://doi.org/10.1093/nar/gky379

Aitken, A. (2006). 14-3-3 proteins: A historic overview. Seminars in Cancer Biology, 16(3), 162–172. https://doi.org/10.1016/j.semcancer.2006.03.005

Akaki, K., Ogata, K., Yamauchi, Y., Iwai, N., Tse, K. M., Hia, F., Mochizuki, A., Ishihama, Y., Mino, T., & Takeuchi, O. (2021). Irak1-dependent regnase-1-14-3-3 complex formation controls regnase-1-mediated mrna decay. ELife, 10. https://doi.org/10.7554/ELIFE.71966

Akira, S., Uematsu, S., & Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell, 124(4), 783–801. https://doi.org/10.1016/j.cell.2006.02.015

Anderson, P. (2010). Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nature Reviews Immunology, 10(1), 24–35. https://doi.org/10.1038/nri2685

Buchan, D. W. A., & Jones, D. T. (2019). The PSIPRED Protein Analysis Workbench: 20 years on. Nucleic Acids Research, 47(W1), W402–W407. https://doi.org/10.1093/nar/gkz297

Carpenter, S., Ricci, E. P., Mercier, B. C., Moore, M. J., & Fitzgerald, K. A. (2014). Post- transcriptional regulation of gene expression in innate immunity. Nature Reviews Immunology, 14(6), 361–376. https://doi.org/10.1038/nri3682

Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., & Zhang, F. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science, 339(6121), 819–823. https://doi.org/10.1126/science.1231143

Davis, M., Hatzubai, A., Andersen, J. S., Ben-Shushan, E., Fisher, G. Z., Yaron, A., Bauskin, A., Mercurio, F., Mann, M., & Ben-Neriah, Y. (2002). Pseudosubstrate regulation of the SCFβ-TrCP ubiquitin ligase by hnRNP-U. Genes and Development, 16(4), 439–451. https://doi.org/10.1101/gad.218702

Fitzgerald, K. A., & Kagan, J. C. (2020). Toll-like Receptors and the Control of Immunity. Cell, 180(6), 1044–1066. https://doi.org/10.1016/j.cell.2020.02.041

Flannery, S. M., Keating, S. E., Szymak, J., & Bowie, A. G. (2011). Human interleukin-1 receptor-associated kinase-2 is essential for toll-like receptor-mediated transcriptional and post-transcriptional regulation of tumor necrosis factor α. Journal of Biological Chemistry, 286(27), 23688–23697. https://doi.org/10.1074/jbc.M111.248351

Fu, H., Coburn, J., & Collier, R. J. (1993). The eukaryotic host factor that activates exoenzyme S of Pseudomonas aeruginosa is a member of the 14-3-3 protein family. Proceedings of the National Academy of Sciences of the United States of America, 90(6), 2320–2324. https://doi.org/10.1073/pnas.90.6.2320

Fujihara, Y., & Ikawa, M. (2014). CRISPR/Cas9-based genome editing in mice by single plasmid injection. In Methods in Enzymology (Vol. 546, Issue C, pp. 319–336). Academic Press Inc. https://doi.org/10.1016/B978-0-12-801185-0.00015-5

Gottipati, S., Rao, N. L., & Fung-Leung, W. P. (2008). IRAK1: A critical signaling mediator of innate immunity. Cellular Signalling, 20(2), 269–276. https://doi.org/10.1016/j.cellsig.2007.08.009

Guo, C. J., Ma, X. K., Xing, Y. H., Zheng, C. C., Xu, Y. F., Shan, L., Zhang, J., Wang, S., Wang, Y., Carmichael, G. G., Yang, L., & Chen, L. L. (2020). Distinct Processing of lncRNAs Contributes to Non-conserved Functions in Stem Cells. Cell, 181(3), 621-636.e22. https://doi.org/10.1016/j.cell.2020.03.006

Hartupee, J., Li, X., & Hamilton, T. (2008). Interleukin 1α-induced NFκB activation and chemokine mRNA stabilization diverge at IRAK. Journal of Biological Chemistry, 283(23), 15689–15693. https://doi.org/10.1074/jbc.M801346200

Hutten, S., & Kehlenbach, R. H. (2007). CRM1-mediated nuclear export: to the pore and beyond.Trends in Cell Biology, 17(4), 193–201. https://doi.org/10.1016/j.tcb.2007.02.003 Iwasaki, H., Takeuchi, O., Teraguchi, S., Matsushita, K., Uehata, T., Kuniyoshi, K., Satoh, T.,Saitoh, T., Matsushita, M., Standley, D. M., & Akira, S. (2011). The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR–IL-1R by controlling degradation of regnase-1. Nature Immunology, 12(12), 1167–1175. https://doi.org/10.1038/ni.2137

Jones, D. T. (1999). Protein secondary structure prediction based on position-specific scoring matrices. Journal of Molecular Biology, 292(2), 195–202. https://doi.org/10.1006/jmbi.1999.3091

Kakiuchi, N., Yoshida, K., Uchino, M., Kihara, T., Akaki, K., Inoue, Y., Kawada, K., Nagayama, S., Yokoyama, A., Yamamoto, S., Matsuura, M., Horimatsu, T., Hirano, T., Goto, N., Takeuchi, Y., Ochi, Y., Shiozawa, Y., Kogure, Y., Watatani, Y., … Ogawa, S. (2020).Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature, 577(7789), 260–265. https://doi.org/10.1038/s41586-019-1856-1

Karlberg, T., Hornyak, P., Pinto, A. F., Milanova, S., Ebrahimi, M., Lindberg, M., Püllen, N., Nordström, A., Löverli, E., Caraballo, R., Wong, E. V., Näreoja, K., Thorsell, A. G., Elofsson, M., De La Cruz, E. M., Björkegren, C., & Schüler, H. (2018). 14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface. Nature Communications, 9(1), 1–11. https://doi.org/10.1038/s41467-018-06194-1

Kollewe, C., Mackensen, A. C., Neumann, D., Knop, J., Cao, P., Li, S., Wesche, H., & Martin, M.U. (2004). Sequential Autophosphorylation Steps in the Interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling. Journal of Biological Chemistry, 279(7), 5227–5236. https://doi.org/10.1074/jbc.M309251200

la Cour, T., Gupta, R., Rapacki, K., Skriver, K., Poulsen, F. M., & Brunak, S. (2003). NESbase version 1.0: A database of nuclear export signals. Nucleic Acids Research, 31(1), 393–396. https://doi.org/10.1093/nar/gkg101

Maquat, L. E., Tarn, W. Y., & Isken, O. (2010). The pioneer round of translation: Features and functions. Cell, 142(3), 368–374. https://doi.org/10.1016/j.cell.2010.07.022

Masters, S. C., Pederson, K. J., Zhang, L., Barbieri, J. T., & Fu, H. (1999). Interaction of 14-3-3 with a nonphosphorylated protein ligand, exoenzyme S of Pseudomonas aeruginosa.Biochemistry, 38(16), 5216–5221. https://doi.org/10.1021/bi982492m

Matsushita, K., Takeuchi, O., Standley, D. M., Kumagai, Y., Kawagoe, T., Miyake, T., Satoh, T., Kato, H., Tsujimura, T., Nakamura, H., & Akira, S. (2009). Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature, 458(7242), 1185– 1190. https://doi.org/10.1038/nature07924

Meerbrey, K. L., Hu, G., Kessler, J. D., Roarty, K., Li, M. Z., Fang, J. E., Herschkowitz, J. I.,Burrows, A. E., Ciccia, A., Sun, T., Schmitt, E. M., Bernardi, R. J., Fu, X., Bland, C. S., Cooper, T. A., Schiff, R., Rosen, J. M., Westbrook, T. F., & Elledge, S. J. (2011). The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo.Proceedings of the National Academy of Sciences of the United States of America, 108(9), 3665–3670. https://doi.org/10.1073/pnas.1019736108

Mino, T., Iwai, N., Endo, M., Inoue, K., Akaki, K., Hia, F., Uehata, T., Emura, T., Hidaka, K., Suzuki, Y., Standley, D. M., Okada-Hatakeyama, M., Ohno, S., Sugiyama, H., Yamashita, A., & Takeuchi, O. (2019). Translation-dependent unwinding of stem–loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs. Nucleic Acids Research. https://doi.org/10.1093/nar/gkz628

Mino, T., Murakawa, Y., Fukao, A., Vandenbon, A., Wessels, H. H., Ori, D., Uehata, T., Tartey, S., Akira, S., Suzuki, Y., Vinuesa, C. G., Ohler, U., Standley, D. M., Landthaler, M., Fujiwara, T., & Takeuchi, O. (2015). Regnase-1 and roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms. Cell, 161(5), 1058–1073. https://doi.org/10.1016/j.cell.2015.04.029

Müller-Mcnicoll, M., & Neugebauer, K. M. (2013). How cells get the message: Dynamic assembly and function of mRNA-protein complexes. Nature Reviews Genetics, 14(4), 275–287. https://doi.org/10.1038/nrg3434

Muslin, A. J., Tanner, J. W., Allen, P. M., & Shaw, A. S. (1996). Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell, 84(6), 889–897. https://doi.org/10.1016/S0092-8674(00)81067-3

Nanki, K., Fujii, M., Shimokawa, M., Matano, M., Nishikori, S., Date, S., Takano, A., Toshimitsu, K., Ohta, Y., Takahashi, S., Sugimoto, S., Ishimaru, K., Kawasaki, K., Nagai, Y., Ishii, R., Yoshida, K., Sasaki, N., Hibi, T., Ishihara, S., … Sato, T. (2020). Somatic inflammatory gene mutations in human ulcerative colitis epithelium. 254 | Nature |, 577. https://doi.org/10.1038/s41586-019-1844-5

Neidel, S., Ren, H., Torres, A. A., & Smith, G. L. (2019). NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation. Proceedings of the National Academy of Sciences of the United States of America, 116(12), 5699–5704. https://doi.org/10.1073/pnas.1813504116

Notredame, C., Higgins, D. G., & Heringa, J. (2000). T-coffee: A novel method for fast and accurate multiple sequence alignment. Journal of Molecular Biology, 302(1), 205–217. https://doi.org/10.1006/jmbi.2000.4042

Ottmann, C., Yasmin, L., Weyand, M., Veesenmeyer, J. L., Diaz, M. H., Palmer, R. H., Francis,M. S., Hauser, A. R., Wittinghofer, A., & Hallberg, B. (2007). Phosphorylation- independent interaction between 14-3-3 and exoenzyme S: From structure to pathogenesis. EMBO Journal, 26(3), 902–913. https://doi.org/10.1038/sj.emboj.7601530

Pennington, K. L., Chan, T. Y., Torres, • Mp, & Andersen, • Jl. (2018). The dynamic and stress- adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context- dependent protein-protein interactions. Oncogene, 37, 5587–5604. https://doi.org/10.1038/s41388-018-0348-3

Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., Tinevez, J. Y., White, D. J., Hartenstein, V., Eliceiri, K., Tomancak, P., & Cardona, A. (2012). Fiji: An open-source platform for biological- image analysis. Nature Methods, 9(7), 676–682. https://doi.org/10.1038/nmeth.2019

Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003). Cytoscape: A software Environment for integrated models of biomolecular interaction networks. Genome Research, 13(11), 2498–2504. https://doi.org/10.1101/gr.1239303

Sugiyama, N., Imamura, H., & Ishihama, Y. (2019). Large-scale Discovery of Substrates of the Human Kinome. Scientific Reports 2019 9:1, 9(1), 1–12. https://doi.org/10.1038/s41598-019-46385-4

Szklarczyk, D., Gable, A. L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., Simonovic, M., Doncheva, N. T., Morris, J. H., Bork, P., Jensen, L. J., & Von Mering, C. (2019). STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Research, 47(D1), D607– D613. https://doi.org/10.1093/nar/gky1131

Takeuchi, O., & Akira, S. (2010). Pattern Recognition Receptors and Inflammation. Cell, 140(6), 805–820. https://doi.org/10.1016/j.cell.2010.01.022

Tanaka, H., Arima, Y., Kamimura, D., Tanaka, Y., Takahashi, N., Uehata, T., Maeda, K., Satoh, T., Murakami, M., & Akira, S. (2019). Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response. Journal of Experimental Medicine,216(6). https://doi.org/10.1084/jem.20181078

Turner, M., & DÍaz-Muñoz, M. D. (2018). RNA-binding proteins control gene expression and cell fate in the immune system review-article. In Nature Immunology (Vol. 19, Issue 2, pp. 120–129). Nature Publishing Group. https://doi.org/10.1038/s41590-017-0028-4

Uehata, T., Iwasaki, H., Vandenbon, A., Matsushita, K., Hernandez-Cuellar, E., Kuniyoshi, K., Satoh, T., Mino, T., Suzuki, Y., Standley, D. M., Tsujimura, T., Rakugi, H., Isaka, Y., Takeuchi, O., & Akira, S. (2013). Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell, 153(5), 1036–1049. https://doi.org/10.1016/j.cell.2013.04.034

van Buuren, N., Burles, K., Schriewer, J., Mehta, N., Parker, S., Buller, R. M., & Barry, M. (2014). EVM005: An Ectromelia-Encoded Protein with Dual Roles in NF-κB Inhibition and Virulence. PLoS Pathogens, 10(8), 1004326. https://doi.org/10.1371/journal.ppat.1004326

Verdoodt, B., Benzinger, A., Popowicz, G. M., Holak, T. A., & Hermeking, H. (2006).Characterization of 14-3-3sigma dimerization determinants: Requirement of homodimerization for inhibition of cell proliferation. Cell Cycle, 5(24), 2920–2926. https://doi.org/10.4161/cc.5.24.3571

Wan, Y., Xiao, H., Affolter, J., Kim, T. W., Bulek, K., Chaudhuri, S., Carlson, D., Hamilton, T., Mazumder, B., Stark, G. R., Thomas, J., & Li, X. (2009). Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. Journal of Biological Chemistry, 284(16), 10367–10375. https://doi.org/10.1074/jbc.M807822200

Waterhouse, A. M., Procter, J. B., Martin, D. M. A., Clamp, M., & Barton, G. J. (2009). Jalview Version 2-A multiple sequence alignment editor and analysis workbench. Bioinformatics, 25(9), 1189–1191. https://doi.org/10.1093/bioinformatics/btp033

Wei, J., Long, L., Zheng, W., Dhungana, Y., Lim, S. A., Guy, C., Wang, Y., Wang, Y. D., Qian,C., Xu, B., Kc, A., Saravia, J., Huang, H., Yu, J., Doench, J. G., Geiger, T. L., & Chi, H. (2019). Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature, 576(7787), 471–476. https://doi.org/10.1038/s41586-019-1821-z

Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S., & Cao, Z. (1997). MyD88: An adapter that recruits IRAK to the IL-1 receptor complex. Immunity, 7(6), 837–847. https://doi.org/10.1016/S1074-7613(00)80402-1

Xu, D., Marquis, K., Pei, J., Fu, S. C., Caʇatay, T., Grishin, N. V., & Chook, Y. M. (2015). LocNES: A computational tool for locating classical NESs in CRM1 cargo proteins. Bioinformatics, 31(9), 1357–1365. https://doi.org/10.1093/bioinformatics/btu826

Xu, J., Peng, W., Sun, Y., Wang, X., Xu, Y., Li, X., Gao, G., & Rao, Z. (2012). Structural study of MCPIP1 N-terminal conserved domain reveals a PIN-like RNase. Nucleic Acids Research, 40(14), 6957–6965. https://doi.org/10.1093/nar/gks359

Yaffe, M. B., Rittinger, K., Volinia, S., Caron, P. R., Aitken, A., Leffers, H., Gamblin, S. J., Smerdon, S. J., & Cantley, L. C. (1997). The structural basis for 14-3-3:phosphopeptide binding specificity. Cell, 91(7), 961–971. https://doi.org/10.1016/S0092-8674(00)80487-0

Yang, Q., Li, K., Huang, X., Zhao, C., Mei, Y., Li, X., Jiao, L., & Yang, H. (2020). lncRNA SLC7A11-AS1 Promotes Chemoresistance by Blocking SCFβ-TRCP-Mediated Degradation of NRF2 in Pancreatic Cancer. Molecular Therapy - Nucleic Acids, 19, 974– 985. https://doi.org/10.1016/j.omtn.2019.11.035

Yasmin, L., Jansson, A. L., Panahandeh, T., Palmer, R. H., Francis, M. S., & Hallberg, B. (2006).Delineation of exoenzyme S residues that mediate the interaction with 14-3-3 and its biological activity. FEBS Journal, 273(3), 638–646. https://doi.org/10.1111/j.1742- 4658.2005.05100.x

Ye, H., Arron, J. R., Lamothe, B., Cirilli, M., Kobayashi, T., Shevde, N. K., Segal, D., Dzivenu, O.K., Vologodskaia, M., Yim, M., Du, K., Singh, S., Pike, J. W., Darnay, B. G., Choi, Y., & Wu,H. (2002). Distinct molecular mechanism for initiating TRAF6 signalling. Nature, 418(6896), 443–447. https://doi.org/10.1038/nature00888

Yokogawa, M., Tsushima, T., Noda, N. N., Kumeta, H., Enokizono, Y., Yamashita, K., Standley,D. M., Takeuchi, O., Akira, S., & Inagaki, F. (2016). Structural basis for the regulation of enzymatic activity of Regnase-1 by domain-domain interactions. Scientific Reports, 6, 22324. https://doi.org/10.1038/srep22324

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文

一発検索!

この論文の関連論文を見る