請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74296
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張智芬(Zee-Fen Chang) | |
dc.contributor.author | I-Chen Tu | en |
dc.contributor.author | 杜宜蓁 | zh_TW |
dc.date.accessioned | 2021-06-17T08:28:30Z | - |
dc.date.available | 2029-08-12 | |
dc.date.copyright | 2019-08-27 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-12 | |
dc.identifier.citation | 1. Lacombe, M.L., Milon, L., Munier, A., Mehus, J.G., Lambeth, D.O. (2000). The human Nm23/ nucleoside diphosphate kinases. J Bioenerg Biomembr 32: 247-258.
2. Jeudy, S., Lartique, A., Claverie, J.M., Abergel, C. (2009). Dissecting the unique nucleotide specificity of mimivirus nucleoside diphosphate kinase. J Virol 83: 7142-7150. 3. Steeg, P.S. (2003). Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer 3: 55-63. 4. Conery, A.R., Sever, S., Harlow, E. (2010). Nucleoside diphosphate kinase Nm23-H1 regulates chromosomal stability by activating the GTPase dynamin during cytokinesis. Proc Natl Acad Sci U.S.A. 107:15461-15466. 5. Boissan, M., et al. (2014). Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Science 344: 1510-1515. 6. Dammai, V., Adryan, B., Lavenburg, K.R., Hsu, T. (2003). Drosophila awd, the homolog of human nm23, regulates FGF receptor levels and functions synergistically with shi/ dynamin during tracheal development. Genes Dev 17: 2812-2824. 7. Miller, J.H., et al. (2000). Escherichia coli strains (ndk) lacking nucleoside diphosphate kinase are powerful mutators for base substitutions and frameshifts in mismatch-repair-deficient strains. Genetics 162: 5-13. 8. McDermott, W.G., et al. (2008). Nm23-H1 homologs suppress tumor cell motility and anchorage independent growth. Clin Exp Metastasis 25: 131-138. 9. Rush-Fuhs, S., Meisenhelder, J., Aslanian, A. Ma, A., Zagorska, A., Stankova, M., Binnie, A., Al-Obeidi, F., Mauger, J., Lemke, G., Yates-III, J.R., Hunter, T. (2015). Monoclonal 1- and 3-phosphohistidine antibodies: new tools to study histidine phosphorylation. Cell 162: 198-210. 10. Di, L., Srivastava, S., Zhdanova, O., Sun, Y., Li, Z., Skolnik, E.Y. (2010). Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation. JBC 285: 38765-38771. 11. Boissan, M., Dabernat, S., Peuchant, E., Schlattner, U., Lascu, I., Lacombe, M.L. (2009). The mammalian Nm23/ NDPK family: from metastasis control to cilia movement. Mol Cell Biochem 329: 51-62. 12. Braun, S., et al. (2007). Novel roles of NM23 proteins in skin homeostasis, repair and disease. Oncogene 26: 532-542. 13. Negroni, A., Venturelli, D., Tanno, B., Amendola, R., Ransac, S., Cesi, V., Calabretta, B., Raschella, G. (2000). Neuroblastoma specific effects of DR-nm23 and its mutant forms on differentiation and apoptosis. Cell Death Differ 7: 843-850. 14. Chen, C.W., et al. (2019). Two separate functions of NME3 critical for cell survival underlie a neurodegeneration disorder. PNAS 116: 566-574. 15. Milon, L. et al. (2000). The human nm23-H4 gene product is a mitochondrial nucleoside diphosphate kinase. J Biol Chem 275: 14264-14272. 16. Tokarska-Schlattner, M., Boissam, M., Munier, A., Borot, C., Mailleau, C., Speer, O., Schlattner, U., Lacombe, M.L. (2008). The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration. J Biol Chem 283: 26198-26207. 17. Tsuiki, H., et al. (1999). A novel human nucleoside diphosphate (NDP) kinase, Nm23-H6, localizes in mitochondria and affects cytokinesis. J Cell Biochem 76: 254-269. 18. Janin, J., Dumas, C., Morera, S., Xu, Y., Meyer, P., Chiadmi, M., Cherfils, J. (2000). Three-dimensional structure of nucleoside diphosphate kinase. J Bioenerg Biomembr 32: 215–225. 19. Lascu, I., and Gonin, P. (2000). The catalytic mechanism of nucleoside diphosphate kinases. J Bioenerg Biomembr 32: 215-225. 20. Wagner, P.D. and Vu, N.D. (1995). Phosphorylation of ATP-citrate lyase by nucleoside diphosphate kinase. J Biol Chem 270: 21758-21764. 21. Hartsough, M.T., Morrison, D.K., Salerno, M., Palmieri, D., Ouatas, T., Mair, M., Patrick, J., Steeg, P.S. (2002). Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J Biol Chem 277: 32389-32399. 22. Srivastava, S., Li, Z., Ko, K., Choudhury, P., Albaqumi, M., Johnson, A.K., Yan, Y., Backer, J.M., Unutmaz, D., Coetzee, W.A., Skolnik, E.Y. (2006). Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Molecular Cell 24: 665-675. 23. Cai, X., Srivastava, S., Surindran, S., Li, Z., Skolnik, E.Y. (2014). Regulation of the epithelial Ca²+ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1. Mol Biol Cell 25: 1244-1250. 24. Steeg, P.S., Bevilacqua, G., Kopper, L., Thorgeirsson, U.P., Talmadge, J.E., Liotta, L.A., Sobel, M.E. (1988). Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80: 200-204. 25. Thakur, R.K., Yadav, V.K., Kumar, P., Chowdhury, S. (2011). Mechanisms of non-metastatic 2 (NME2)-mediated control of metastasis across tumor types. Naunyn Schmiedebergs Arch Pharmacol 384: 397-406. 26. Tso, P.H., Wang, Y., Yung, L.Y., Tong, Y., Lee, M.M., Wong, Y.H. (2013). RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras. Cell Signal 25: 1064-1074. 27. Wieland, T., Hippe, H.J., Ludwig, K., Zhou, X.B., Korth, M., and Klumpp, S. (2010). Reversible histidine phosphorylation in mammalian cells: a teeter-totter formed by nucleoside diphosphate kinase and protein histidine phosphatase 1. Methods Enzymol 471: 379–402. 28. Venturelli, D., et al. (1995). Overexpression of DR-nm23, a protein encoded by a member of the nm23 gene family, inhibits granulocyte differentiation and induces apoptosis in 32Dc13 myeloid cells. Proc Natl Acad Sci USA 92: 7435-7439. 29. Tsao, N., Yang, Y.C., Deng, Y.J., Chang, Z.F. (2016). The direct interation of NME3 with Tip60 in DNA repair. Biochem J 473: 1237-1245. 30. Abu-Taha, I.H., et al. (2017). Nucleoside diphosphate kinase-C suppresses cAMP formation in human heart failure. Circulation 135: 881-897. 31. Flentie, K., Gonzalez, C., Kocher, B., Wang, Y., Zhu, H., Marasa, J., Piwnica-Worms, D. (2018). Nucleoside diphosphate kinase-3 (NME3) enhances TLR5-induced NF-κB activation. Mol Cancer Res 16: 986-999. 32. Wang, C.H., et al. (2012). A shRNA functional screen reveals Nme 6 and Nme 7 are crucial for embryonic stem cell renewal. Stem Cells 30: 2199-2211. 33. Koshiba, T., Detmer, S.A., Kaiser, J.T., Chen, H., McCaffery, J.M., Chan, D.C. (2004). Structural basis of mitochondrial tethering by mitofusion complexes. Science 305: 858-862. 34. Moehle E.A., et al. (2019). Mitochondrial proteostasis in the context of cellular and organismal health and aging. J Biol Chem 294: 5396-5407. 35. Itakura, E., Zavodszky, E., Shao, S., Wohlever, M.L., Keenan, R.J., Hegde, R.S. (2016). Ubiquilins chaperone and triage mitochondrial membrane proteins for degradation. Mol Cell 63: 21-33. 36. Hjerpe, R., Bett, J.S., Keuss, M.J., et al. UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome. Cell 166: 935-949. 37. Lecker, S.H., Goldberg, A.L., Mitch, W.E. (2006). Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17: 1807-1819. 38. Glickman, M.H., and Ciechanover, A. (2002). The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82: 373-428. 39. Pickart, C.M. (2001). Mechanisms underlying ubiquitination. Ann Rev Biochem 70: 503-533. 40. Weissman, A.M. (2001). Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2: 169- 178. 41. Ciechanover, A., and Iwai, K. (2004). The ubiquitin system: from basic mechanisms to the patient bed. IUBMB Life 56: 193-201. 42. Matsuda, A., Suzuki, Y., Honda, G., Muramatsu, S., Matsuzaki, O., Nagano, Y., Doi, T., Shimotohno, K., Harada, T., Nishida, E., et al. (2003). Large-scale identification and characterization of human genes that activate NF-kappa B and MAPK signaling pathways. Oncogene 22: 3307-3318. 43. Li, W., et al. (2008). Genome-wide and functional annotation of human E3 Ubiquitin Ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS ONE 3: e1487. 44. Neuspiel, M., Schauss, A.C., Braschi, E., Zunino, R., Rippstein, P., Rachubinski, R.A., Andrade-Navarro, M.A., McBride, H.M. (2008). Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr Biol 18: 102-108. 45. Zhang, B., et al. (2008). GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth. Cell Research 18:900-910. 46. Yun, J., Puri, R., Yang, H., Lizzio, M.A., Wu, C., Sheng, Z.H., Guo, M. (2014). MUL1 acts in parallel to the PINK1/ parkin pathway in regulating mitofusin and compensates for loss of PINK2/ parkin. Elife 3: 1-26. 47. Bae, S., et al. (2012). AKT is negatively regulated by the MULAN E3 ligase. Cell Res 22: 873-885. 48. Jung, Y.S., Qian, Y., and Chen, X. (2011). The p73 tumor suppressor is targeted by Pirh2 RING finger E3 ubiquitin ligase for the proteasome-dependent degradation. J Biol Chem 286: 35388-35395. 49. Li, J., et al. (2015). Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy. Basic Science Brief Report 11: 1216-1228. 50. Ni, G., Konno, H., Barber, G.N. (2017). Ubiquitination of STING at lysine 224 controls IRF3 activation. Sci Immunol 2: eaah7119. 51. Peng J., Ren, K.D., Yang, J., Luo, X.J. (2016). Mitochondrial E3 ubiquitin ligase 1: A key enzyme in regulation of mitochondrial dynamics and functions. Mitochondrion 28: 49-53. 52. Zungu, M., Schisler, J., Willis, M.S. (2011). All the little pieces. -Regulation of mitochondrial fusion and fission by ubiquitin and small ubiquitin-like modifer and their potential relevance in the heart. Circ J 75: 2513–2521. 53. Braschi, E., Zunino, R., and McBride, H.M. (2009). MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission. EMBO Rep 10: 748-754. 54. Prudent, J., et al. (2015). MAPL SUMOylation of Drp1 stabilizes an ER/ mitochondrial platform required for cell death. Molecular Cell 59: 941-955. 55. Al-Mehdi, A.B., Pastukh, V.M., Swiger, B.M., Reed, D.J., Patel, M.R., Bardwell, G.C., Pastukh, V.V., Alexeyev, M.F., Gillespie, M.N. (2012). Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci signal 5: ra47. 56. Rush-Fuhs, S., Hunter, T. (2017). pHisphorylation; The emergence of histidine phosphorylation as a reversible regulatory modification. Curr Opin Cell Biol 45: 8-16. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74296 | - |
dc.description.abstract | 核苷二磷酸激酶3 (NME3) 屬於核苷二磷酸激酶 (NDPK) 家族,其家族能夠透過組氨酸激酶 (histidine kinase) 活性催化乒乓反應 (Ping-pong reaction),使磷酸根 (phosphate) 從核苷三磷酸轉移至核苷二磷酸。我們先前的研究發現,NME3參與在粒線體融合蛋白 (Mitofusin) 所調控粒線體融合的過程中。NME3表現量的抑低會導致粒線體呈現片段狀的型態。NME3的過量表現則會造成粒線體簇集於細胞核周圍,顯示NME3的蛋白質表現量對於粒線體形態的重要性。本研究中,我證明NME3是一個容易經由泛素化所降解的高度不穩定蛋白質。我也發現,引導NME3座落於粒線體外膜的N端氨基酸對於此降解過程是必要的。更進一步的研究發現,位於粒線體外膜上的粒線體泛素連接酶1 (MUL1) 負責NME3的泛素化及蛋白質降解。MUL1的E3連接酶活性在低氧時受到氧化壓力的影響而下降,使NME3的表現量上升最終導致粒線體簇集於細胞核周圍。有趣的是,NME3也會透過組胺酸激酶活性磷酸化MUL1的H319位點來抑制其活性,顯示兩個蛋白質之間有互相調控的作用。因此,喪失酵素活性的NME3 H135Q突變型比野生型NME3具有更短的蛋白質半衰期。根據以上結果,NME3和MUL1之間具有相互拮抗的關係,在粒線體型態的調控中扮演相反的角色。 | zh_TW |
dc.description.abstract | NME3, a member of nucleoside diphosphate kinase (NDPK) family, is capable of transferring a phosphate from a nucleoside triphosphate to a nucleoside diphosphate by a ping-pong reaction via its histidine kinase activity. Our laboratory has previously demonstrated that NME3 has a function in stimulation of MFN-mediated mitochondrial fusion. Knockdown of NME3 increases fragmented mitochondria while overexpression of NME3 leads to mitochondrial clustering, suggesting the importance of expression level of NME3 in maintaining mitochondrial dynamics. Using an inducible system, I presented evidence that NME3 is a highly unstable protein degraded by ubiquitin-proteasome system dependent on its N-terminus-mediated mitochondrial anchoring. MUL1, an E3 ligase localized on outer membrane of mitochondria, was identified to be responsible for ubiquitination and proteolysis of NME3. In response to hypoxia, NME3 is upregulated to mediate mitochondrial clustering. The E3 ligase activity of MUL1 is reduced by hypoxia-induced oxidative stress. Most interestingly, NME3 also suppresses MUL1 activity through phosphorylation of H319 via histidine kinase activity. As such, catalytic-dead mutant has a shorter half-life than wild-type of NME3. Therefore, the reciprocal regulation between NME3 and MUL1 exerts an opposite control in mitochondrial morphology. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T08:28:30Z (GMT). No. of bitstreams: 1 ntu-108-R06448014-1.pdf: 13178097 bytes, checksum: d93c1dd0d3fd481dc52eec6c0f88125b (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 論文摘要 iii Abstract iv Table of contents 1 Introduction 3 1. Nucleoside diphosphate kinase (NDPK, NME, Nm23) family 3 1.1 NME isoforms 5 1.2 NME structure 6 1.3 NME enzymatic function 7 1.4 The disparate function of NME3 in mitochondria 8 2. Mitochondrial proteostasis 9 2.1 Regulating Mitochondrial proteostasis by protein degradation 10 2.2 Ubiquitin/ Proteasome System (UPS) 11 2.3 Mitochondrial E3 ligase 1 (MUL1, MULAN, MAPL, GIDE) 12 Materials and Methods 14 Results 33 Susceptibility of NME3 to ubiquitin/ proteolysis is dependent on mitochondrial localization 33 Mitochondrial ubiquitin ligase 1 (MUL1) controls the protein level of NME3 34 In vitro and in vivo polyubiquitination of NME3 by MUL1 35 Complex formation of NME3 and MUL1 35 MUL1 determines the expression level and stability of NME3 36 Hypoxia suppresses proteolytic control of NME3 and promotes mitochondrial clustering 36 The activity of MUL1 is attenuated by hypoxia-induced oxidative stress 38 The catalytic function of NME3 suppresses the activity of MUL1 by H319 phosphorylation 39 Catalytic-dead NME3 is more susceptible to MUL1-mediated degradation 40 Discussion 42 Figures 45 References 61 Appendix 70 | |
dc.language.iso | en | |
dc.title | 核苷二磷酸激酶3與粒線體泛素連接酶1相互拮抗調控粒線體之型態 | zh_TW |
dc.title | NME3-MUL1 opposition in regulation of mitochondrial morphology | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 劉雅雯(Ya-Wen Liu),陳瑞華(Ruey-Hwa Chen),陳鴻震(Hong-Chen Chen) | |
dc.subject.keyword | 核?二磷酸激?3,粒線體泛素連接?1,粒線體,泛素化, | zh_TW |
dc.subject.keyword | NME3,MUL1,mitochondria,ubiquitination,UPS,proteolysis, | en |
dc.relation.page | 73 | |
dc.identifier.doi | 10.6342/NTU201903201 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-08-13 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-108-1.pdf 目前未授權公開取用 | 12.87 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。