請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19663
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳瑞華 | |
dc.contributor.author | Chin-Chih Liu | en |
dc.contributor.author | 劉晉志 | zh_TW |
dc.date.accessioned | 2021-06-08T02:12:07Z | - |
dc.date.copyright | 2016-02-15 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-01-19 | |
dc.identifier.citation | Adams, J., Kelso, R., and Cooley, L. (2000). The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol 10, 17-24.
Alemu, E.A., Lamark, T., Torgersen, K.M., Birgisdottir, A.B., Larsen, K.B., Jain, A., Olsvik, H., Overvatn, A., Kirkin, V., and Johansen, T. (2012). ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J Biol Chem 287, 39275-39290. Angers, S., Li, T., Yi, X., MacCoss, M.J., Moon, R.T., and Zheng, N. (2006). Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443, 590-593. Antonioli, M., Albiero, F., Nazio, F., Vescovo, T., Perdomo, A.B., Corazzari, M., Marsella, C., Piselli, P., Gretzmeier, C., Dengjel, J., et al. (2014). AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics. Dev Cell 31, 734-746. Arai, T., Kasper, J.S., Skaar, J.R., Ali, S.H., Takahashi, C., and DeCaprio, J.A. (2003). Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Proc Natl Acad Sci U S A 100, 9855-9860. Axe, E.L., Walker, S.A., Manifava, M., Chandra, P., Roderick, H.L., Habermann, A., Griffiths, G., and Ktistakis, N.T. (2008). Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182, 685-701. Bodemann, B.O., Orvedahl, A., Cheng, T., Ram, R.R., Ou, Y.H., Formstecher, E., Maiti, M., Hazelett, C.C., Wauson, E.M., Balakireva, M., et al. (2011). RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144, 253-267. Boyden, L.M., Choi, M., Choate, K.A., Nelson-Williams, C.J., Farhi, A., Toka, H.R., Tikhonova, I.R., Bjornson, R., Mane, S.M., Colussi, G., et al. (2012). Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482, 98-102. Bulatov, E., and Ciulli, A. (2015). Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation. Biochem J 467, 365-386. Canning, P., Cooper, C.D., Krojer, T., Murray, J.W., Pike, A.C., Chaikuad, A., Keates, T., Thangaratnarajah, C., Hojzan, V., Ayinampudi, V., et al. (2013). Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. J Biol Chem 288, 7803-7814. Chan, E.Y., Kir, S., and Tooze, S.A. (2007). siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J Biol Chem 282, 25464-25474. Chan, E.Y., Longatti, A., McKnight, N.C., and Tooze, S.A. (2009). Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol 29, 157-171. Chang, Y.Y., and Neufeld, T.P. (2009). An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol Biol Cell 20, 2004-2014. Chen, C.H., Wang, W.J., Kuo, J.C., Tsai, H.C., Lin, J.R., Chang, Z.F., and Chen, R.H. (2005). Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J 24, 294-304. Chen, D., Gao, F., Li, B., Wang, H., Xu, Y., Zhu, C., and Wang, G. (2010). Parkin mono-ubiquitinates Bcl-2 and regulates autophagy. J Biol Chem 285, 38214-38223. Chen, G.C., Lee, J.Y., Tang, H.W., Debnath, J., Thomas, S.M., and Settleman, J. (2008). Genetic interactions between Drosophila melanogaster Atg1 and paxillin reveal a role for paxillin in autophagosome formation. Autophagy 4, 37-45. Choi, A.M., Ryter, S.W., and Levine, B. (2013a). Autophagy in human health and disease. N Engl J Med 368, 651-662. Choi, A.M., Ryter, S.W., and Levine, B. (2013b). Autophagy in human health and disease. N Engl J Med 368, 1845-1846. Ci, Y., Shi, K., An, J., Yang, Y., Hui, K., Wu, P., Shi, L., and Xu, C. (2014). ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells. Cell Death Dis 5, e1542. Cirak, S., von Deimling, F., Sachdev, S., Errington, W.J., Herrmann, R., Bonnemann, C., Brockmann, K., Hinderlich, S., Lindner, T.H., Steinbrecher, A., et al. (2010). Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy. Brain 133, 2123-2135. Conaway, R.C., and Conaway, J.W. (2002). The von Hippel-Lindau tumor suppressor complex and regulation of hypoxia-inducible transcription. Adv Cancer Res 85, 1-12. Di Bartolomeo, S., Corazzari, M., Nazio, F., Oliverio, S., Lisi, G., Antonioli, M., Pagliarini, V., Matteoni, S., Fuoco, C., Giunta, L., et al. (2010). The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol 191, 155-168. Diao, J., Liu, R., Rong, Y., Zhao, M., Zhang, J., Lai, Y., Zhou, Q., Wilz, L.M., Li, J., Vivona, S., et al. (2015). ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520, 563-566. Dias, D.C., Dolios, G., Wang, R., and Pan, Z.Q. (2002). CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex. Proc Natl Acad Sci U S A 99, 16601-16606. Dooley, H.C., Razi, M., Polson, H.E., Girardin, S.E., Wilson, M.I., and Tooze, S.A. (2014). WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell 55, 238-252. Dorsey, F.C., Rose, K.L., Coenen, S., Prater, S.M., Cavett, V., Cleveland, J.L., and Caldwell-Busby, J. (2009). Mapping the phosphorylation sites of Ulk1. J Proteome Res 8, 5253-5263. Dunlop, E.A., Hunt, D.K., Acosta-Jaquez, H.A., Fingar, D.C., and Tee, A.R. (2011). ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7, 737-747. Egan, D.F., Shackelford, D.B., Mihaylova, M.M., Gelino, S., Kohnz, R.A., Mair, W., Vasquez, D.S., Joshi, A., Gwinn, D.M., Taylor, R., et al. (2011). Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456-461. Fan, W., Nassiri, A., and Zhong, Q. (2011). Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). Proc Natl Acad Sci U S A 108, 7769-7774. Feng, Y., He, D., Yao, Z., and Klionsky, D.J. (2014). The machinery of macroautophagy. Cell Res 24, 24-41. Fogel, A.I., Dlouhy, B.J., Wang, C., Ryu, S.W., Neutzner, A., Hasson, S.A., Sideris, D.P., Abeliovich, H., and Youle, R.J. (2013). Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy. Mol Cell Biol 33, 3675-3688. Friedman, J.S., Ray, J.W., Waseem, N., Johnson, K., Brooks, M.J., Hugosson, T., Breuer, D., Branham, K.E., Krauth, D.S., Bowne, S.J., et al. (2009). Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. Am J Hum Genet 84, 792-800. Fujita, N., Hayashi-Nishino, M., Fukumoto, H., Omori, H., Yamamoto, A., Noda, T., and Yoshimori, T. (2008a). An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol Biol Cell 19, 4651-4659. Fujita, N., Itoh, T., Omori, H., Fukuda, M., Noda, T., and Yoshimori, T. (2008b). The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19, 2092-2100. Fullgrabe, J., Lynch-Day, M.A., Heldring, N., Li, W., Struijk, R.B., Ma, Q., Hermanson, O., Rosenfeld, M.G., Klionsky, D.J., and Joseph, B. (2013). The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature 500, 468-471. Furukawa, M., He, Y.J., Borchers, C., and Xiong, Y. (2003). Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol 5, 1001-1007. Gammoh, N., Florey, O., Overholtzer, M., and Jiang, X. (2013). Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy. Nat Struct Mol Biol 20, 144-149. Ganley, I.G., Lam du, H., Wang, J., Ding, X., Chen, S., and Jiang, X. (2009). ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284, 12297-12305. Gao, W., Shen, Z., Shang, L., and Wang, X. (2011). Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death. Cell Death Differ 18, 1598-1607. Geng, J., and Klionsky, D.J. (2008). The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. 'Protein modifications: beyond the usual suspects' review series. EMBO Rep 9, 859-864. Geyer, R., Wee, S., Anderson, S., Yates, J., and Wolf, D.A. (2003). BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases. Mol Cell 12, 783-790. Groisman, R., Polanowska, J., Kuraoka, I., Sawada, J., Saijo, M., Drapkin, R., Kisselev, A.F., Tanaka, K., and Nakatani, Y. (2003). The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113, 357-367. Gupta, V.A., and Beggs, A.H. (2014). Kelch proteins: emerging roles in skeletal muscle development and diseases. Skelet Muscle 4, 11. Gwinn, D.M., Shackelford, D.B., Egan, D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E., and Shaw, R.J. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30, 214-226. Hahn, N., Dietz, C.T., Kuhl, S., Vossmerbaeumer, U., and Kroll, J. (2012). KLEIP deficiency in mice causes progressive corneal neovascular dystrophy. Invest Ophthalmol Vis Sci 53, 3260-3268. Hailey, D.W., Rambold, A.S., Satpute-Krishnan, P., Mitra, K., Sougrat, R., Kim, P.K., and Lippincott-Schwartz, J. (2010). Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141, 656-667. Hamasaki, M., Furuta, N., Matsuda, A., Nezu, A., Yamamoto, A., Fujita, N., Oomori, H., Noda, T., Haraguchi, T., Hiraoka, Y., et al. (2013). Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389-393. Hanada, T., Noda, N.N., Satomi, Y., Ichimura, Y., Fujioka, Y., Takao, T., Inagaki, F., and Ohsumi, Y. (2007). The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282, 37298-37302. Hara, T., Ishida, H., Raziuddin, R., Dorkhom, S., Kamijo, K., and Miki, T. (2004). Novel kelch-like protein, KLEIP, is involved in actin assembly at cell-cell contact sites of Madin-Darby canine kidney cells. Mol Biol Cell 15, 1172-1184. Hara, T., and Mizushima, N. (2009). Role of ULK-FIP200 complex in mammalian autophagy: FIP200, a counterpart of yeast Atg17? Autophagy 5, 85-87. Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889. Hara, T., Takamura, A., Kishi, C., Iemura, S., Natsume, T., Guan, J.L., and Mizushima, N. (2008). FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181, 497-510. He, C., and Klionsky, D.J. (2009). Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43, 67-93. He, Y.J., McCall, C.M., Hu, J., Zeng, Y., and Xiong, Y. (2006). DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev 20, 2949-2954. Higa, L.A., Wu, M., Ye, T., Kobayashi, R., Sun, H., and Zhang, H. (2006). CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat Cell Biol 8, 1277-1283. Higashimura, Y., Terai, T., Yamaji, R., Mitani, T., Ogawa, M., Harada, N., Inui, H., and Nakano, Y. (2011). Kelch-like 20 up-regulates the expression of hypoxia-inducible factor-2alpha through hypoxia- and von Hippel-Lindau tumor suppressor protein-independent regulatory mechanisms. Biochem Biophys Res Commun 413, 201-205. Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, S., Natsume, T., Takehana, K., Yamada, N., et al. (2009a). Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20, 1981-1991. Hosokawa, N., Sasaki, T., Iemura, S., Natsume, T., Hara, T., and Mizushima, N. (2009b). Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5, 973-979. Hu, J., McCall, C.M., Ohta, T., and Xiong, Y. (2004). Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol 6, 1003-1009. Inoki, K., Zhu, T., and Guan, K.L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590. Itakura, E., Kishi, C., Inoue, K., and Mizushima, N. (2008). Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19, 5360-5372. Itakura, E., and Mizushima, N. (2010). Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6, 764-776. Jager, S., Bucci, C., Tanida, I., Ueno, T., Kominami, E., Saftig, P., and Eskelinen, E.L. (2004). Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117, 4837-4848. Jiang, P., and Mizushima, N. (2014). Autophagy and human diseases. Cell Res 24, 69-79. Jiao, H., Su, G.Q., Dong, W., Zhang, L., Xie, W., Yao, L.M., Chen, P., Wang, Z.X., Liou, Y.C., and You, H. (2015). Chaperone-like protein p32 regulates ULK1 stability and autophagy. Cell Death Differ 22, 1812-1823. Jin, J., Arias, E.E., Chen, J., Harper, J.W., and Walter, J.C. (2006). A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell 23, 709-721. Johansen, T., and Lamark, T. (2011). Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279-296. Joo, J.H., Dorsey, F.C., Joshi, A., Hennessy-Walters, K.M., Rose, K.L., McCastlain, K., Zhang, J., Iyengar, R., Jung, C.H., Suen, D.F., et al. (2011). Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol Cell 43, 572-585. Joshi, A., Iyengar, R., Joo, J.H., Li-Harms, X.J., Wright, C., Marino, R., Winborn, B.J., Phillips, A., Temirov, J., Sciarretta, S., et al. (2015). Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1. Cell Death Differ. Jung, C.H., Jun, C.B., Ro, S.H., Kim, Y.M., Otto, N.M., Cao, J., Kundu, M., and Kim, D.H. (2009). ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 20, 1992-2003. Jung, C.H., Seo, M., Otto, N.M., and Kim, D.H. (2011). ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7, 1212-1221. Kamura, T., Koepp, D.M., Conrad, M.N., Skowyra, D., Moreland, R.J., Iliopoulos, O., Lane, W.S., Kaelin, W.G., Jr., Elledge, S.J., Conaway, R.C., et al. (1999). Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284, 657-661. Kamura, T., Maenaka, K., Kotoshiba, S., Matsumoto, M., Kohda, D., Conaway, R.C., Conaway, J.W., and Nakayama, K.I. (2004). VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes Dev 18, 3055-3065. Kang, R., Zeh, H.J., Lotze, M.T., and Tang, D. (2011). The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18, 571-580. Kather, J.N., Friedrich, J., Woik, N., Sticht, C., Gretz, N., Hammes, H.P., and Kroll, J. (2014). Angiopoietin-1 is regulated by miR-204 and contributes to corneal neovascularization in KLEIP-deficient mice. Invest Ophthalmol Vis Sci 55, 4295-4303. Kaufmann, A., Beier, V., Franquelim, H.G., and Wollert, T. (2014). Molecular mechanism of autophagic membrane-scaffold assembly and disassembly. Cell 156, 469-481. Kawakami, T., Chiba, T., Suzuki, T., Iwai, K., Yamanaka, K., Minato, N., Suzuki, H., Shimbara, N., Hidaka, Y., Osaka, F., et al. (2001). NEDD8 recruits E2-ubiquitin to SCF E3 ligase. EMBO J 20, 4003-4012. Kemp, M.G., Lindsey-Boltz, L.A., and Sancar, A. (2015). UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1). J Biol Chem 290, 12184-12194. Kim, I.F., Mohammadi, E., and Huang, R.C. (1999). Isolation and characterization of IPP, a novel human gene encoding an actin-binding, kelch-like protein. Gene 228, 73-83. Kim, J., Kundu, M., Viollet, B., and Guan, K.L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13, 132-141. Kohroki, J., Nishiyama, T., Nakamura, T., and Masuho, Y. (2005). ASB proteins interact with Cullin5 and Rbx2 to form E3 ubiquitin ligase complexes. FEBS Lett 579, 6796-6802. Komander, D. (2009). The emerging complexity of protein ubiquitination. Biochem Soc Trans 37, 937-953. Komander, D., and Rape, M. (2012). The ubiquitin code. Annu Rev Biochem 81, 203-229. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169, 425-434. Konno, H., Konno, K., and Barber, G.N. (2013). Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155, 688-698. Kraft, C., Kijanska, M., Kalie, E., Siergiejuk, E., Lee, S.S., Semplicio, G., Stoffel, I., Brezovich, A., Verma, M., Hansmann, I., et al. (2012). Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy. EMBO J 31, 3691-3703. Kroemer, G., Marino, G., and Levine, B. (2010). Autophagy and the integrated stress response. Mol Cell 40, 280-293. Kulathu, Y., and Komander, D. (2012). Atypical ubiquitylation - the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol 13, 508-523. Kuroyanagi, H., Yan, J., Seki, N., Yamanouchi, Y., Suzuki, Y., Takano, T., Muramatsu, M., and Shirasawa, T. (1998). Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment. Genomics 51, 76-85. Lamb, C.A., Yoshimori, T., and Tooze, S.A. (2013). The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol 14, 759-774. Lazarou, M., Sliter, D.A., Kane, L.A., Sarraf, S.A., Wang, C., Burman, J.L., Sideris, D.P., Fogel, A.I., and Youle, R.J. (2015). The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309-314. Lee, E.J., and Tournier, C. (2011). The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy. Autophagy 7, 689-695. Lee, J., and Zhou, P. (2012). Pathogenic Role of the CRL4 Ubiquitin Ligase in Human Disease. Front Oncol 2, 21. Lee, Y.R., Yuan, W.C., Ho, H.C., Chen, C.H., Shih, H.M., and Chen, R.H. (2010a). The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses. Embo J 29, 1748-1761. Lee, Y.R., Yuan, W.C., Ho, H.C., Chen, C.H., Shih, H.M., and Chen, R.H. (2010b). The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses. EMBO J 29, 1748-1761. Levine, B., and Kroemer, G. (2008). Autophagy in the pathogenesis of disease. Cell 132, 27-42. Liang, C. (2010). Negative regulation of autophagy. Cell Death Differ 17, 1807-1815. Liang, C., Lee, J.S., Inn, K.S., Gack, M.U., Li, Q., Roberts, E.A., Vergne, I., Deretic, V., Feng, P., Akazawa, C., et al. (2008). Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 10, 776-787. Lin, M.Y., Lin, Y.M., Kao, T.C., Chuang, H.H., and Chen, R.H. (2011). PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth. J Cell Biol 193, 985-994. Lin, S.Y., Li, T.Y., Liu, Q., Zhang, C., Li, X., Chen, Y., Zhang, S.M., Lian, G., Liu, Q., Ruan, K., et al. (2012). GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336, 477-481. Liu, J., Xia, H., Kim, M., Xu, L., Li, Y., Zhang, L., Cai, Y., Norberg, H.V., Zhang, T., Furuya, T., et al. (2011a). Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147, 223-234. Liu, J., Xia, H., Kim, M., Xu, L., Li, Y., Zhang, L., Cai, Y., Norberg, H.V., Zhang, T., Furuya, T., et al. (2011b). Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147, 223-234. Liu, Y., and Levine, B. (2015). Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 22, 367-376. Lu, Q., Yang, P., Huang, X., Hu, W., Guo, B., Wu, F., Lin, L., Kovacs, A.L., Yu, L., and Zhang, H. (2011). The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. Dev Cell 21, 343-357. Mahrour, N., Redwine, W.B., Florens, L., Swanson, S.K., Martin-Brown, S., Bradford, W.D., Staehling-Hampton, K., Washburn, M.P., Conaway, R.C., and Conaway, J.W. (2008). Characterization of Cullin-box sequences that direct recruitment of Cul2-Rbx1 and Cul5-Rbx2 modules to Elongin BC-based ubiquitin ligases. J Biol Chem 283, 8005-8013. Matsunaga, K., Morita, E., Saitoh, T., Akira, S., Ktistakis, N.T., Izumi, T., Noda, T., and Yoshimori, T. (2010). Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol 190, 511-521. Matsunaga, K., Saitoh, T., Tabata, K., Omori, H., Satoh, T., Kurotori, N., Maejima, I., Shirahama-Noda, K., Ichimura, T., Isobe, T., et al. (2009). Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11, 385-396. McIntire, S.L., Garriga, G., White, J., Jacobson, D., and Horvitz, H.R. (1992). Genes necessary for directed axonal elongation or fasciculation in C. elegans. Neuron 8, 307-322. McMahon, M., Thomas, N., Itoh, K., Yamamoto, M., and Hayes, J.D. (2006). Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a 'tethering' mechanism: a two-site interaction model for the Nrf2-Keap1 complex. J Biol Chem 281, 24756-24768. Mercer, C.A., Kaliappan, A., and Dennis, P.B. (2009). A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 5, 649-662. Mizushima, N. (2010). The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22, 132-139. Mizushima, N. (2011). Autophagy in protein and organelle turnover. Cold Spring Harb Symp Quant Biol 76, 397-402. Mizushima, N., Kuma, A., Kobayashi, Y., Yamamoto, A., Matsubae, M., Takao, T., Natsume, T., Ohsumi, Y., and Yoshimori, T. (2003). Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 116, 1679-1688. Mizushima, N., and Levine, B. (2010). Autophagy in mammalian development and differentiation. Nat Cell Biol 12, 823-830. Mochizuki, H., Toda, H., Ando, M., Kurusu, M., Tomoda, T., and Furukubo-Tokunaga, K. (2011). Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain. PLoS One 6, e19632. Mukhopadhyay, S., Das, D.N., Panda, P.K., Sinha, N., Naik, P.P., Bissoyi, A., Pramanik, K., and Bhutia, S.K. (2015). Autophagy protein Ulk1 promotes mitochondrial apoptosis through reactive oxygen species. Free Radic Biol Med 89, 311-321. Nacak, T.G., Alajati, A., Leptien, K., Fulda, C., Weber, H., Miki, T., Czepluch, F.S., Waltenberger, J., Wieland, T., Augustin, H.G., et al. (2007). The BTB-Kelch protein KLEIP controls endothelial migration and sprouting angiogenesis. Circ Res 100, 1155-1163. Nakai, A., Yamaguchi, O., Takeda, T., Higuchi, Y., Hikoso, S., Taniike, M., Omiya, S., Mizote, I., Matsumura, Y., Asahi, M., et al. (2007). The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13, 619-624. Nakatogawa, H., Ohbayashi, S., Sakoh-Nakatogawa, M., Kakuta, S., Suzuki, S.W., Kirisako, H., Kondo-Kakuta, C., Noda, N.N., Yamamoto, H., and Ohsumi, Y. (2012). The autophagy-related protein kinase Atg1 interacts with the ubiquitin-like protein Atg8 via the Atg8 family interacting motif to facilitate autophagosome formation. J Biol Chem 287, 28503-28507. Nakatogawa, H., Suzuki, K., Kamada, Y., and Ohsumi, Y. (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10, 458-467. Nazio, F., Strappazzon, F., Antonioli, M., Bielli, P., Cianfanelli, V., Bordi, M., Gretzmeier, C., Dengjel, J., Piacentini, M., Fimia, G.M., et al. (2013). mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol 15, 406-416. Neel, B.A., Lin, Y., and Pessin, J.E. (2013). Skeletal muscle autophagy: a new metabolic regulator. Trends Endocrinol Metab 24, 635-643. Nishimura, T., Kaizuka, T., Cadwell, K., Sahani, M.H., Saitoh, T., Akira, S., Virgin, H.W., and Mizushima, N. (2013). FIP200 regulates targeting of Atg16L1 to the isolation membrane. EMBO Rep 14, 284-291. O'Farrell, F., Rusten, T.E., and Stenmark, H. (2013). Phosphoinositide 3-kinases as accelerators and brakes of autophagy. FEBS J 280, 6322-6337. Ogura, K., Wicky, C., Magnenat, L., Tobler, H., Mori, I., Muller, F., and Ohshima, Y. (1994). Caenorhabditis elegans unc-51 gene required for axonal elongation encodes a novel serine/threonine kinase. Genes Dev 8, 2389-2400. Ogura, T., Tong, K.I., Mio, K., Maruyama, Y., Kurokawa, H., Sato, C., and Yamamoto, M. (2010). Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci U S A 107, 2842-2847. Orenstein, S.J., and Cuervo, A.M. (2010). Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol 21, 719-726. Orlicky, S., Tang, X., Willems, A., Tyers, M., and Sicheri, F. (2003). Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell 112, 243-256. Orsi, A., Razi, M., Dooley, H.C., Robinson, D., Weston, A.E., Collinson, L.M., and Tooze, S.A. (2012). Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 23, 1860-1873. Pause, A., Peterson, B., Schaffar, G., Stearman, R., and Klausner, R.D. (1999). Studying interactions of four proteins in the yeast two-hybrid system: structural resemblance of the pVHL/elongin BC/hCUL-2 complex with the ubiquitin ligase complex SKP1/cullin/F-box protein. Proc Natl Acad Sci U S A 96, 9533-9538. Petroski, M.D., and Deshaies, R.J. (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6, 9-20. Pickart, C.M. (2004). Back to the future with ubiquitin. Cell 116, 181-190. Pintard, L., Willems, A., and Peter, M. (2004). Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family. EMBO J 23, 1681-1687. Pintard, L., Willis, J.H., Willems, A., Johnson, J.L., Srayko, M., Kurz, T., Glaser, S., Mains, P.E., Tyers, M., Bowerman, B., et al. (2003). The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 425, 311-316. Platta, H.W., Abrahamsen, H., Thoresen, S.B., and Stenmark, H. (2012). Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1. Biochem J 441, 399-406. Polson, H.E., de Lartigue, J., Rigden, D.J., Reedijk, M., Urbe, S., Clague, M.J., and Tooze, S.A. (2010). Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6, 506-522. Proikas-Cezanne, T., Takacs, Z., Donnes, P., and Kohlbacher, O. (2015). WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome. J Cell Sci 128, 207-217. Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C., and Rubinsztein, D.C. (2010). Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 12, 747-757. Robinson, D.N., and Cooley, L. (1997). Drosophila kelch is an oligomeric ring canal actin organizer. J Cell Biol 138, 799-810. Rogov, V., Dotsch, V., Johansen, T., and Kirkin, V. (2014). Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell 53, 167-178. Rong, Y., McPhee, C.K., Deng, S., Huang, L., Chen, L., Liu, M., Tracy, K., Baehrecke, E.H., Yu, L., and Lenardo, M.J. (2011). Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc Natl Acad Sci U S A 108, 7826-7831. Russell, R.C., Tian, Y., Yuan, H., Park, H.W., Chang, Y.Y., Kim, J., Kim, H., Neufeld, T.P., Dillin, A., and Guan, K.L. (2013). ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15, 741-750. Sala, D., Ivanova, S., Plana, N., Ribas, V., Duran, J., Bach, D., Turkseven, S., Laville, M., Vidal, H., Karczewska-Kupczewska, M., et al. (2014). Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes. J Clin Invest 124, 1914-1927. Saleiro, D., Mehrotra, S., Kroczynska, B., Beauchamp, E.M., Lisowski, P., Majchrzak-Kita, B., Bhagat, T.D., Stein, B.L., McMahon, B., Altman, J.K., et al. (2015). Central role of ULK1 in type I interferon signaling. Cell Rep 11, 605-617. Sandri, M., Coletto, L., Grumati, P., and Bonaldo, P. (2013). Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies. J Cell Sci 126, 5325-5333. Sarikas, A., Hartmann, T., and Pan, Z.Q. (2011). The cullin protein family. Genome Biol 12, 220. Schink, K.O., Raiborg, C., and Stenmark, H. (2013). Phosphatidylinositol 3-phosphate, a lipid that regulates membrane dynamics, protein sorting and cell signalling. Bioessays 35, 900-912. Schmid, M.F., Agris, J.M., Jakana, J., Matsudaira, P., and Chiu, W. (1994). Three-dimensional structure of a single filament in the Limulus acrosomal bundle: scruin binds to homologous helix-loop-beta motifs in actin. J Cell Biol 124, 341-350. Schwander, M., Leu, M., Stumm, M., Dorchies, O.M., Ruegg, U.T., Schittny, J., and Muller, U. (2003). Beta1 integrins regulate myoblast fusion and sarcomere assembly. Dev Cell 4, 673-685. Shang, L., Chen, S., Du, F., Li, S., Zhao, L., and Wang, X. (2011). Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A 108, 4788-4793. Shi, C.S., and Kehrl, J.H. (2010). TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci Signal 3, ra42. Soltysik-Espanola, M., Rogers, R.A., Jiang, S., Kim, T.A., Gaedigk, R., White, R.A., Avraham, H., and Avraham, S. (1999). Characterization of Mayven, a novel actin-binding protein predominantly expressed in brain. Mol Biol Cell 10, 2361-2375. Stogios, P.J., and Prive, G.G. (2004). The BACK domain in BTB-kelch proteins. Trends Biochem Sci 29, 634-637. Sun, Q., Fan, W., Chen, K., Ding, X., Chen, S., and Zhong, Q. (2008). Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 105, 19211-19216. Suttangkakul, A., Li, F., Chung, T., and Vierstra, R.D. (2011). The ATG1/ATG13 protein kinase complex is both a regulator and a target of autophagic recycling in Arabidopsis. Plant Cell 23, 3761-3779. Tanaka, Y., Guhde, G., Suter, A., Eskelinen, E.L., Hartmann, D., Lullmann-Rauch, R., Janssen, P.M., Blanz, J., von Figura, K., and Saftig, P. (2000). Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902-906. Tang, H.W., Wang, Y.B., Wang, S.L., Wu, M.H., Lin, S.Y., and Che | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19663 | - |
dc.description.abstract | 當細胞面臨壓力時,會藉由細胞自噬反應降解胞內物質,以幫助細胞生存與 維持細胞及組織的恆定性。過去對細胞自噬的研究多聚焦於自噬的發生,對此過 程如何終止所知甚少。ULK1 是一個引發細胞自噬反應的絲氨酸/蘇氨酸蛋白激酶。 在本篇研究中我們發現 ULK1 是 Cul3-KLHL20 泛素接合酶的基質,在細胞自噬發 生後,KLHL20 會辨認被自我進行磷酸化修飾的 ULK1,對其進行泛素化修飾並造 成蛋白降解。因此,細胞自噬可以藉由引發 KLHL20 對 ULK1 的降解,來限制反應 的強度以及反應持續的時間。除了 ULK1 以外,在缺乏養分的環境下,細胞自噬反 應也會透過 KLHL20,直接或間接的造成 ATG13,VPS34,Beclin-1,以及 ATG14 蛋白的降解。因此,KLHL20 可以透過降解 ULK1 以及 VPS34 複合體的相關蛋白, 來促使細胞自噬反應的終止。在長期缺乏養分的環境下,若阻礙 KLHL20 對細胞 自噬的調控功能使反應無法終止,會造成細胞死亡的增加。另外,在小鼠的骨骼 肌中剔除 KLHL20 基因,則會加劇糖尿病所引發的肌肉萎縮。我們的研究發現了 KLHL20 在細胞自噬反應之終止以及病理上的重要性。 | zh_TW |
dc.description.abstract | Autophagy, a cellular self-eating mechanism, is important for maintaining cell survival and tissue homeostasis in various stressed conditions. Although the molecular mechanism of autophagy induction has been well studied, how cells terminate autophagy process remains elusive. Here, we show that ULK1, a serine/threonine kinase critical for autophagy initiation, is a substrate of the Cul3-KLHL20 ubiquitin ligase. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis. This autophagy-stimulated, KLHL20-dependent ULK1 degradation restrains the amplitude and duration of autophagy. Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism. Impairment of KLHL20-mediated regulation of autophagy dynamics potentiates starvation-induced cell death and aggravates diabetes-associated muscle atrophy. Our study identifies a key role of KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:12:07Z (GMT). No. of bitstreams: 1 ntu-105-D98b46009-1.pdf: 100166572 bytes, checksum: 2a4b2b7bd23d1d6f621250a95c6bf0c1 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 中 文 摘 要 ............................................................................................1
Abstract.............................................................................................2 Table of contents...................................................................................3 Literature Review................................................................................11 1. Autophagy....................................................................................11 1.1. Types....................................................................................11 1.2. Physiological significances..........................................................12 1.3. Molecular mechanisms...............................................................12 1.3.1. Initiation and nucleation......................................................13 1.3.2. Expansion.......................................................................14 1.3.3. Maturation......................................................................15 1.3.4. Termination.....................................................................16 2. ULK1.........................................................................................16 2.1. ULK1 family and domain structures................................................16 2.2. Regulation of ULK1 in autophagy..................................................18 2.2.1. Phosphorylation...............................................................19 2.2.2. Acetylation.....................................................................20 2.2.3. Ubiquitination..................................................................20 2.2.4. Interaction......................................................................21 2.3. ULK1 downstream effectors in autophagy........................................22 2.3.1. VPS34 complex...............................................................22 2.3.2. ATG9...........................................................................23 2.3.3. Other putative downstream effectors.......................................23 2.4. ULK1 in mitophagy..................................................................23 2.5. Nonautophagic functions............................................................24 2.5.1. Neuronal development........................................................24 2.5.2. Innate immune responses.....................................................25 2.5.3. Cell death.......................................................................26 3. Ubiquitination...............................................................................26 3.1. Ubiquitination cascade...............................................................27 3.2. Different topologies of ubiquitination..............................................27 3.3. Types of ubiquitin ligases............................................................28 3.4. Cullin-RING ligases..................................................................29 3.5. KLHL protein family.................................................................31 3.6. KLHL20................................................................................32 4.Ubiquitin-dependent regulation of autophagy...........................................34 4.1. Ubiquitin-proteasome system in autophagy regulation..........................34 4.2. Non-proteolytic ubiquitination in autophagy regulation.........................34 Introduction.......................................................................................36 Results..............................................................................................40 ULK1 is a substrate of the Cul3-KLHL20 ubiquitin ligase..............................40 KLHL20 mediates starvation-induced ULK1 ubiquitination and degradation to contribute to autophagy termination.........................................................41 ULK1 autophosphorylation promotes its ubiquitination and degradation by KLHL20.........................................................................................42 ULK1 autophosphorylation contributes to autophagy termination.....................44 KLHL20 controls autophagy-induced turnover of multiple ULK1 and VPS34 complex subunits...............................................................................44 Impairment of KLHL20-mediated autophagy termination promotes cell death and diabetes-associated muscle atrophy.........................................................46 Discussion..........................................................................................49 Material and methods...........................................................................54 Plasmids.........................................................................................54 Antibodies and reagents.......................................................................54 Cell culture, transfection, and treatment....................................................55 RNA interference and lentiviral transduction..............................................55 Immunoprecipitation and GST pull down assays..........................................56 Ubiquitination assays..........................................................................56 Kinase assay....................................................................................57 Immunofluorescence analysis................................................................57 Autophagy assays..............................................................................58 Cell death assay................................................................................58 Yeast two-hybrid screen......................................................................59 Generation of muscle-specific KLHL20 KO mice........................................59 Mice treatments.................................................................................60 Immunofluorescence analysis of muscle sections.........................................60 TEM analysis...................................................................................61 Figures.............................................................................................62 Fig. 1. Endougenous KLHL20 binds to endogenous ULK1..............................62 Fig. 2. KLHL20 interacts with ULK1 through the kelch-repeat domain...............63 Fig. 3. KLHL20-based Cul3 complex promotes ULK1 ubiquitination in vivo........64 Fig. 4. Purified Roc1-Cul3-KLHL20 complex promotes ULK1 ubiquitination in vitro..............................................................................................65 Fig. 5. KLHL20 promotes ULK1 degradation through Cul3 association..............66 Fig. 6. KLHL20 promotes ULK1 proteasomal degradation..............................67 Fig. 7. KLHL20 increases the turnover of ULK1 protein................................68 Fig. 8. Cul3 mediates ULK1 ubiquitination................................................69 Fig. 9. KLHL20 mediates starvation-induced ULK1 degradation......................70 Fig. 10. KLHL20 mediates starvation-induced K48-linked ubiquitination of ULK1............................................................................................71 Fig. 11. KLHL20 depletion leads to persistent increment of LC3 puncta in starvation........................................................................................72 Fig. 12. KLHL20 depletion results in a persistent elevation of ATG16 puncta during the 8 hr-starvation period.....................................................................73 Fig. 13. KLHL20-depleted cells display a persistent elevation of LC3-II during the entire starvation period........................................................................75 Fig. 14. KLHL20 depletion enhances the autophagic degradation of p62 and total LC3 in starvation ..............................................................................76 Fig. 15. KLHL20 mediates ULK1 downregulation in response to amino acid deprivation......................................................................................77 Fig. 16. KLHL20 depletion leads to sustained increment of LC3 puncta in response to amino acid deprivation.....................................................................78 Fig. 17. KLHL20 depletion cells exhibit a persistent elevation of LC3-II during amino acid deprivation........................................................................79 Fig. 18. Starvation enhances the interaction between ULK1 and KLHL20............80 Fig. 19. Starvation does not affect the autoubiquitination capability of KLHL20....81 Fig. 20. The interaction between KLHL20 and ULK1 is phosphorylation-dependent and enhanced by starvation...................................................................82 Fig. 21. The AMPK phosphorylation-mimetic mutant of ULK1 (5D) does not exhibit an enhanced interaction with KLHL20 in fed cells.......................................83 Fig. 22. The mutant that mimics (DD) or blocks (AA) autophosphorylation at S1042/T1046 displays comparable kinase catalytic activity with wild type ULK1...84 Fig. 23. DD mutant binds KLHL20 stronger than wild type ULK1 in fed conditions.......................................................................................85 Fig. 24. DD mutant is more susceptible to Cul3-KLHL20 ubiquitin ligase-mediated ubiquitination and KLH20-mediated degradation than wild type ULK1...............86 Fig. 25. DD mutant displays a faster turnover than wild type ULK1 in reconstituted cells in nutrient-rich conditions..............................................................87 Fig. 26. Starvation fails to promote the association of ULK1AA mutant with KLHL20.........................................................................................88 Fig. 27. AA mutant of ULK1 is refractory to starvation-induced ubiquitination and degradation......................................................................................89 Fig. 28. Starvation-induced ubiquitination and degradation of AA and kinase-dead (K46I) mutants of ULK1 are impaired......................................................90 Fig. 29. AA mutant of ULK1 is resistant to amino acid deprivation-induced degradation......................................................................................91 Fig. 30. Reconstitution with AA mutant results in a more persistent autophagosome formation in response to starvation than wild type ULK1................................92 Fig. 31. Reconstitution with AA mutant results in a more sustained autophagosome formation in response to amino acid deprivation than wild type ULK1...............94 Fig. 32. Reconstitution with AA mutant results in a more persistent induction of ATG16 puncta during prolonged starvation than wild type ULK1.....................96 Fig. 33. ULK1AA mutant reconstitution enhances degradations of p62 and LC3 in response to prolonged starvation or amino acid deprivation.............................98 Fig. 34. KLHL20-mediated ULK1 degradation leads to ATG13 downregulation in starvation........................................................................................99 Fig. 35. KLHL20 mediates starvation-induced VPS34 and Beclin-1 degradation...100 Fig. 36. Purified Roc1-Cul3-KLHL20 complex can’t catalyze ATG13 ubiquitination in vitro..........................................................................................101 Fig. 37. KLHL20 mediates starvation-induced K48-ubiquitination of Beclin-1 and VP34...........................................................................................102 Fig. 38. The binding of KLHL20 to Beclin1 and VPS34 are enhanced upon prolonged starvation.........................................................................103 Fig. 39. Purified Roc1-Cul3-KLHL20 complex promotes the ubiquitination of Beclin-1 purified from fed or starved cells to a similar extent in vitro...............104 Fig. 40. Purified Roc1-Cul3-KLHL20 complex promotes the ubiquitination of VPS34 purified from fed or starved cells to a similar extent in vitro..................105 Fig. 41. KLHL20-positive puncta are frequently closely associated with ATG16 puncta..........................................................................................106 Fig. 42. KLHL20 and Beclin-1 exhibit partial colocalization in ATG16-positive phagophore....................................................................................107 Fig. 43. ATG14-mediated phagophore targeting of VPS34 complex facilitates the recruitment of Beclin-1 and VPS34 to KLHL20 in prolonged starvation............108 Fig. 44. Starvation-induced VPS34 and Beclin-1 ubiquitination and degradation are impaired in ATG14 mutant-reconstituted cells..........................................109 Fig. 45. ULK1 depletion abrogates starvation-induced ubiquitination and degradation of Beclin-1 and VPS34......................................................................110 Fig. 46. ATG14 is downregulated in prolonged starvation through a KLHL20-dependent manner................................................................111 Fig. 47. Purified Roc1-Cul3-KLHL20 complex fails to catalyze ATG14 ubiquitination in vitro........................................................................112 Fig. 48. Starvation induces a higher level of cell death in ULK1-depleted cells reconstituted with AA mutant than wild type ULK1.....................................113 Fig. 49. KLHL20 depletion enhances autophagy-induced cell death in prolonged starvation.......................................................................................114 Fig. 50. Schematic presentation of wild type and targeted allele of KLHL20 before and after recombination.....................................................................115 Fig. 51. The deletion of floxed sequences from genomic DNA of skeletal muscles.........................................................................................116 Fig. 52. KLHL20 mRNA levels in tissues of homozygous mice.......................117 Fig. 53. KLHL20 expression levels in skeletal muscles of control or KLHL20 KO mice.............................................................................................118 Fig. 54. STZ administration similarly elevates blood glucose levels in control and KLHL20 KO mice...........................................................................119 Fig. 55. KLHL20 KO mice are more susceptible to STZ-induced reductions in muscle weight and cross-sectional area of muscle fibers than control mice.........120 Fig. 56. KLHL20 KO mice show higher levels of LC3-II in muscles than control mice upon diabetes induction...............................................................121 Fig. 57. KLHL20 KO mice display lower levels of p62 in muscles than control mice upon diabetes induction.....................................................................122 Fig. 58. Components of ULK1 and VPS34 complex are accumulated to higher levels in the muscles of diabetic KLHL20 KO mice than control mice......................123 Fig. 59. Electron microscopy analysis revealed an elevation of autophagosome/autolysosome-related structures in the muscles of KLHL20 KO mice than in control mice after STZ treatment..................................................124 Fig. 60. KLHL20 KO mice and control mice display similar reductions in muscle weight and cross-sectional area of muscle fibers caused by STZ-induced diabetes in the presence of chloroquine.................................................................125 Fig. 61. Model for KLHL20-mediated autophagy termination and its physiological and pathological impacts....................................................................126 Appendix.........................................................................................127 Appendix 1. List of genes whose products were identified as putative KLHL20-interacting partners by yeast two-hybrid screen..............................127 Appendix 2: The putative degrons of KLHL20 in ULK1, Beclin-1, and VPS34...128 Appendix 3: The putative degrons of KLHL20 in ULK1 are evolutionarily conserved......................................................................................129 Abbreviations.....................................................................................130 References.......................................................................................135 | |
dc.language.iso | en | |
dc.title | Cul3-KLHL20 泛素接合酶透過調控 ULK1 與 VPS34 複合體的降解來控制細胞自噬反應的終止 | zh_TW |
dc.title | Cul3-KLHL20 ubiquitin ligase governs the turnover of ULK1 and VPS34 complexes to control autophagy termination | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳光超,黃偉邦,楊維元,蔡亭芬 | |
dc.subject.keyword | KLHL20,ULK1,Beclin-1,VPS34,細胞自噬,泛素化, | zh_TW |
dc.subject.keyword | KLHL20,ULK1,Beclin-1,VPS34,autophagy,ubiquitination, | en |
dc.relation.page | 158 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2016-01-21 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-105-1.pdf 目前未授權公開取用 | 97.82 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。