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標題: 家禽里奧病毒p17及σA蛋白調控autophagy、proteasome、glycolysis及TCA cycle以利於病毒複製
Regulation of autophagy, proteasome, glycolysis and TCA cycle by avian reovirus p17 and σA proteins benefiting virus replication
作者: 紀佩宜
Pei-I Chi
關鍵字: 家禽里奧病毒;自體吞噬作用;蛋白酶體;三羧酸循環;三磷酸腺苷;Avian reovirus;ARV;autophagy;proteasome;ATP;TCA cycle;glutaminolysis;HIF-1α;mTORC1;LC3-II
引用: 1. Jones, R. C. (2000) Avian reovirus infections. Rev Sci Tech 19, 614-625. 2. van der Heide, L. (2000) The history of avian reovirus. Avian Dis 44, 638-641. 3. Huang, W. R., Chiu, H. C., Liao, T. L., Chuang, K. P., Shih, W. L., and Liu, H. J. (2015) Avian reovirus protein p17 functions as a nucleoporin Tpr suppressor leading to activation of p53, p21 and PTEN and inactivation of PI3K/AKT/mTOR and ERK signaling pathways. PLoS One 10, e0133699. 4. Prentice, E., Jerome, W. G., Yoshimori, T., Mizushima, N., and Denison, M. R. (2004) Coronavirus replication complex formation utilizes components of cellular autophagy. J Biol Chem 279, 10136-10141. 5. Nandi, D., Tahiliani, P., Kumar, A., and Chandu, D. (2006) The ubiquitin-proteasome system. J Biosci 31, 137-155. 6. Peters, J. M., Franke, W. W., and Kleinschmidt, J. A. (1994) Distinct 19 S and 20 S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm. J Biol Chem 269, 7709-7718. 7. Wang, J., and Maldonado, M. A. (2006) The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases. Cell Mol Immunol 3, 255-261. 8. Wullschleger, S., Loewith, R., and Hall, M. N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484. 9. Fingar, D. C., and Blenis, J. (2004) Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23, 3151-3171. 10. Wang, R. C., Wei, Y., An, Z., Zou, Z., Xiao, G., Bhagat, G., White, M., Reichelt, J., and Levine, B. (2012) Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956-959. 11. Huang, W. R., Chi, P. I., Chiu, H. C., Hsu, J. L., Nielsen, B. L., Liao, T. L., and Liu, H. J. (2017) Avian reovirus p17 and sigmaA act cooperatively to downregulate Akt by suppressing mTORC2 and CDK2/cyclin A2 and upregulating proteasome PSMB6. Sci Rep 7, 5226. 12. Ritter, J. B., Wahl, A. S., Freund, S., Genzel, Y., and Reichl, U. (2010) Metabolic effects of influenza virus infection in cultured animal cells: Intra- and extracellular metabolite profiling. BMC Syst Biol 4, 61. 13. Thai, M., Graham, N. A., Braas, D., Nehil, M., Komisopoulou, E., Kurdistani, S. K., McCormick, F., Graeber, T. G., and Christofk, H. R. (2014) Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication. Cell Metab 19, 694-701. 14. Xiao, L., Hu, Z. Y., Dong, X., Tan, Z., Li, W., Tang, M., Chen, L., Yang, L., Tao, Y., Jiang, Y., Li, J., Yi, B., Li, B., Fan, S., You, S., Deng, X., Hu, F., Feng, L., Bode, A. M., Dong, Z., Sun, L. Q., and Cao, Y. (2014) Targeting Epstein-Barr virus oncoprotein LMP1-mediated glycolysis sensitizes nasopharyngeal carcinoma to radiation therapy. Oncogene 33, 4568-4578. 15. Li, X. B., Gu, J. D., and Zhou, Q. H. (2015) Review of aerobic glycolysis and its key enzymes - new targets for lung cancer therapy. Thorac Cancer 6, 17-24. 16. Ramiere, C., Rodriguez, J., Enache, L. S., Lotteau, V., Andre, P., and Diaz, O. (2014) Activity of hexokinase is increased by its interaction with hepatitis C virus protein NS5A. J Virol 88, 3246-3254. 17. Yu, Y., Maguire, T. G., and Alwine, J. C. (2014) ChREBP, a glucose-responsive transcriptional factor, enhances glucose metabolism to support biosynthesis in human cytomegalovirus-infected cells. Proc Natl Acad Sci U S A 111, 1951-1956. 18. A.M.A. Archives of DermatologyAbrantes, J. L., Alves, C. M., Costa, J., Almeida, F. C., Sola-Penna, M., Fontes, C. F., and Souza, T. M. (2012) Herpes simplex type 1 activates glycolysis through engagement of the enzyme 6-phosphofructo-1-kinase (PFK-1). Biochim Biophys Acta 1822, 1198-1206. 19. Fontaine, K. A., Sanchez, E. L., Camarda, R., and Lagunoff, M. (2015) Dengue virus induces and requires glycolysis for optimal replication. J Virol 89, 2358-2366. 20. Ogawa, M., Takemoto, Y., Sumi, S., Inoue, D., Kishimoto, N., Takamune, N., Shoji, S., Suzu, S., and Misumi, S. (2015) ATP generation in a host cell in early-phase infection is increased by upregulation of cytochrome c oxidase activity via the p2 peptide from human immunodeficiency virus type 1 Gag. Retrovirology 12, 97. 21. Munger, J., Bajad, S. U., Coller, H. A., Shenk, T., and Rabinowitz, J. D. (2006) Dynamics of the cellular metabolome during human cytomegalovirus infection. PLoS Pathog 2, e132. 22. Goodwin, C. M., Xu, S., and Munger, J. (2015) Stealing the keys to the kitchen: Viral manipulation of the host cell metabolic network. Trends Microbiol 23, 789-798. 23. Su, M. A., Huang, Y. T., Chen, I. T., Lee, D. Y., Hsieh, Y. C., Li, C. Y., Ng, T. H., Liang, S. Y., Lin, S. Y., Huang, S. W., Chiang, Y. A., Yu, H. T., Khoo, K. H., Chang, G. D., Lo, C. F., and Wang, H. C. (2014) An invertebrate Warburg effect: a shrimp virus achieves successful replication by altering the host metabolome via the PI3K-Akt-mTOR pathway. PLoS Pathog 10, e1004196. 24. Fontaine, K. A., Camarda, R., and Lagunoff, M. (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88, 4366-4374. 25. Vastag, L., Koyuncu, E., Grady, S. L., Shenk, T. E., and Rabinowitz, J. D. (2011) Divergent effects of human cytomegalovirus and herpes simplex virus-1 on cellular metabolism. PLoS Pathog 7, e1002124. 26. Chen, W. T., Wu, Y. L., Chen, T., Cheng, C. S., Chan, H. L., Chou, H. C., Chen, Y. W., and Yin, H. S. (2014) Proteomics analysis of the DF-1 chicken fibroblasts infected with avian reovirus strain S1133. PLoS One 9, e92154. 27. Imamura, H., Nhat, K. P., Togawa, H., Saito, K., Iino, R., Kato-Yamada, Y., Nagai, T., and Noji, H. (2009) Visualization of ATP levels inside single living cells with fluorescence resonance energy transfer-based genetically encoded indicators. Proc. Natl. Acad. Sci. USA 106, 15651-15656. 28. Betz, C., and Hall, M. N. (2013) Where is mTOR and what is it doing there? J Cell Biol 203, 563-574. 29. Land, S. C., and Tee, A. R. (2007) Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem 282, 20534-20543. 30. Kappler, M., Pabst, U., Rot, S., Taubert, H., Wichmann, H., Schubert, J., Bache, M., Weinholdt, C., Immel, U. D., Grosse, I., Vordermark, D., and Eckert, A. W. (2017) Normoxic accumulation of HIF1alpha is associated with glutaminolysis. Clin Oral Investig 21, 211-224. 31. Benavente, J., and Martinez-Costas, J. (2007) Avian reovirus: structure and biology. Virus Res 123, 105-119. 32. Liu, H. J., Lee, L. H., Hsu, H. W., Kuo, L. C., and Liao, M. H. (2003) Molecular evolution of avian reovirus: evidence for genetic diversity and reassortment of the S-class genome segments and multiple cocirculating lineages. Virology 314, 336-349. 33. Spandidos, D. A., and Graham, A. F. (1976) Physical and chemical characterization of an avian reovirus. J Virol 19, 968-976. 34. Costas, C., Martinez-Costas, J., Bodelon, G., and Benavente, J. (2005) The second open reading frame of the avian reovirus S1 gene encodes a transcription-dependent and CRM1-independent nucleocytoplasmic shuttling protein. J Virol 79, 2141-2150. 35. Shih, W. L., Hsu, H. W., Liao, M. H., Lee, L. H., and Liu, H. J. (2004) Avian reovirus sigmaC protein induces apoptosis in cultured cells. Virology 321, 65-74. 36. Liu, H. J., Lin, P. Y., Lee, J. W., Hsu, H. Y., and Shih, W. L. (2005) Retardation of cell growth by avian reovirus p17 through the activation of p53 pathway. Biochem Biophys Res Commun 336, 709-715. 37. Chiu, H. C., Huang, W. R., Liao, T. L., Chi, P. I., Nielsen, B. L., Liu, J. H., and Liu, H. J. (2018) Mechanistic insights into avian reovirus p17-modulated suppression of cell-cycle CDK/cyclin complexes and enhancement of p53 and cyclin H interaction. J Biol Chem doi: 10.1074/jbc.RA118.002341. 38. Yin, H. S., Shien, J. H., and Lee, L. H. (2000) Synthesis in Escherichia coli of avian reovirus core protein varsigmaA and its dsRNA-binding activity. Virology 266, 33-41. 39. Nibert, M. L., Dermody, T. S., and Fields, B. N. (1990) Structure of the reovirus cell-attachment protein: a model for the domain organization of sigma 1. J Virol 64, 2976-2989. 40. Gonzalez-Lopez, C., Martinez-Costas, J., Esteban, M., and Benavente, J. (2003) Evidence that avian reovirus sigmaA protein is an inhibitor of the double-stranded RNA-dependent protein kinase. J Gen Virol 84, 1629-1639. 41. Vazquez-Iglesias, L., Lostale-Seijo, I., Martinez-Costas, J., and Benavente, J. (2009) Avian reovirus sigmaA localizes to the nucleolus and enters the nucleus by a nonclassical energy- and carrier-independent pathway. J Virol 83, 10163-10175. 42. Huang, P. H., Li, Y. J., Su, Y. P., Lee, L. H., and Liu, H. J. (2005) Epitope mapping and functional analysis of sigma A and sigma NS proteins of avian reovirus. Virology 332, 584-595. 43. Ji, W. T., Chulu, J. L., Lin, F. L., Li, S. K., Lee, L. H., and Liu, H. J. (2008) Suppression of protein expression of three avian reovirus S-class genome segments by RNA interference. Vet Microbiol 129, 252-261. 44. Xu, W., Patrick, M. K., Hazelton, P. R., and Coombs, K. M. (2004) Avian reovirus temperature-sensitive mutant tsA12 has a lesion in major core protein sigmaA and is defective in assembly. J Virol 78, 11142-11151. 45. Grande, A., Rodriguez, E., Costas, C., Everitt, E., and Benavente, J. (2000) Oligomerization and cell-binding properties of the avian reovirus cell-attachment protein sigmaC. Virology 274, 367-377. 46. Chen, Y. T., Lin, C. H., Ji, W. T., Li, S. K., and Liu, H. J. (2008) Proteasome inhibition reduces avian reovirus replication and apoptosis induction in cultured cells. J Virol Methods 151, 95-100. 47. Martinez-Costas, J., Grande, A., Varela, R., Garcia-Martinez, C., and Benavente, J. (1997) Protein architecture of avian reovirus S1133 and identification of the cell attachment protein. J Virol 71, 59-64. 48. Huang, W. R., Wang, Y. C., Chi, P. I., Wang, L., Wang, C. Y., Lin, C. H., and Liu, H. J. (2011) Cell entry of avian reovirus follows a caveolin-1-mediated and dynamin-2-dependent endocytic pathway that requires activation of p38 mitogen-activated protein kinase (MAPK) and Src signaling pathways as well as microtubules and small GTPase Rab5 protein. J Biol Chem 286, 30780-30794. 49. Levine, B., and Kroemer, G. (2008) Autophagy in the pathogenesis of disease. Cell 132, 27-42. 50. Deretic, V., and Levine, B. (2009) Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5, 527-549. 51. Berkova, Z., Crawford, S. E., Trugnan, G., Yoshimori, T., Morris, A. P., and Estes, M. K. (2006) Rotavirus NSP4 induces a novel vesicular compartment regulated by calcium and associated with viroplasms. J Virol 80, 6061-6071. 52. Taylor, M. P., and Kirkegaard, K. (2007) Modification of cellular autophagy protein LC3 by poliovirus. J Virol 81, 12543-12553. 53. Lee, D. Y., and Sugden, B. (2008) The LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis. Blood 111, 2280-2289. 54. Zhou, X., and Munger, K. (2009) Expression of the human papillomavirus type 16 E7 oncoprotein induces an autophagy-related process and sensitizes normal human keratinocytes to cell death in response to growth factor deprivation. Virology 385, 192-197. 55. Kumar, S. H., and Rangarajan, A. (2009) Simian virus 40 small T antigen activates AMPK and triggers autophagy to protect cancer cells from nutrient deprivation. J Virol 83, 8565-8574. 56. Su, W. C., Chao, T. C., Huang, Y. L., Weng, S. C., Jeng, K. S., and Lai, M. M. (2011) Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J Virol 85, 10561-10571. 57. Mizushima, N., and Yoshimori, T. (2007) How to interpret LC3 immunoblotting. Autophagy 3, 542-545. 58. Suzuki, K., Kirisako, T., Kamada, Y., Mizushima, N., Noda, T., and Ohsumi, Y. (2001) The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 20, 5971-5981. 59. Mizushima, N., Sugita, H., Yoshimori, T., and Ohsumi, Y. (1998) A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem 273, 33889-33892. 60. Mizushima, N., Yoshimori, T., and Ohsumi, Y. (2003) Role of the Apg12 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 35, 553-561. 61. Tanida, I., Ueno, T., and Kominami, E. (2004) LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 36, 2503-2518. 62. Kihara, A., Kabeya, Y., Ohsumi, Y., and Yoshimori, T. (2001) Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep 2, 330-335. 63. Gannage, M., Dormann, D., Albrecht, R., Dengjel, J., Torossi, T., Ramer, P. C., Lee, M., Strowig, T., Arrey, F., Conenello, G., Pypaert, M., Andersen, J., Garcia-Sastre, A., and Munz, C. (2009) Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes. Cell Host Microbe 6, 367-380. 64. Kyei, G. B., Dinkins, C., Davis, A. S., Roberts, E., Singh, S. B., Dong, C., Wu, L., Kominami, E., Ueno, T., Yamamoto, A., Federico, M., Panganiban, A., Vergne, I., and Deretic, V. (2009) Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J Cell Biol 186, 255-268. 65. Orvedahl, A., Alexander, D., Talloczy, Z., Sun, Q., Wei, Y., Zhang, W., Burns, D., Leib, D. A., and Levine, B. (2007) HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23-35. 66. E, X., Hwang, S., Oh, S., Lee, J. S., Jeong, J. H., Gwack, Y., Kowalik, T. F., Sun, R., Jung, J. U., and Liang, C. (2009) Viral Bcl-2-mediated evasion of autophagy aids chronic infection of gammaherpesvirus 68. PLoS Pathog 5, e1000609. 67. Lee, J. S., Li, Q., Lee, J. Y., Lee, S. H., Jeong, J. H., Lee, H. R., Chang, H., Zhou, F. C., Gao, S. J., Liang, C., and Jung, J. U. (2009) FLIP-mediated autophagy regulation in cell death control. Nat Cell Biol 11, 1355-1362. 68. Wong, J., Zhang, J., Si, X., Gao, G., Mao, I., McManus, B. M., and Luo, H. (2008) Autophagosome supports coxsackievirus B3 replication in host cells. J Virol 82, 9143-9153. 69. Sir, D., Liang, C., Chen, W. L., Jung, J. U., and Ou, J. H. (2008) Perturbation of autophagic pathway by hepatitis C virus. Autophagy 4, 830-831. 70. Sir, D., and Ou, J. H. (2010) Autophagy in viral replication and pathogenesis. Mol Cells 29, 1-7. 71. Thorpe, L. M., Yuzugullu, H., and Zhao, J. J. (2015) PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15, 7-24. 72. Vanhaesebroeck, B., Stephens, L., and Hawkins, P. (2012) PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol 13, 195-203. 73. Burke, J. E., and Williams, R. L. (2015) Synergy in activating class I PI3Ks. Trends Biochem Sci 40, 88-100. 74. Laplante, M., and Sabatini, D. M. (2012) mTOR signaling in growth control and disease. Cell 149, 274-293. 75. Dibble, C. C., and Cantley, L. C. (2015) Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 25, 545-555. 76. Howell, J. J., Ricoult, S. J., Ben-Sahra, I., and Manning, B. D. (2013) A growing role for mTOR in promoting anabolic metabolism. Biochem Soc Trans 41, 906-912. 77. Ricoult, S. J., and Manning, B. D. (2013) The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep 14, 242-251. 78. Dunlop, E. A., and Tee, A. R. (2014) mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol 36, 121-129. 79. Collins, G. A., and Goldberg, A. L. (2017) The logic of the 26S proteasome. Cell 169, 792-806. 80. Zhao, J., Zhai, B., Gygi, S. P., and Goldberg, A. L. (2015) mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc. Natl. Acad. Sci. USA 112, 15790-15797. 81. Kish-Trier, E., and Hill, C. P. (2013) Structural biology of the proteasome. Annu Rev Biophys 42, 29-49. 82. Naifeh, J., and Bhimji, S. S. (2018) Biochemistry, carbohydrate, aerobic glycolysis. in StatPearls, Treasure Island (FL). Available from: 83. Sanchez, E. L., and Lagunoff, M. (2015) Viral activation of cellular metabolism. Virology 479-480, 609-618. 84. Zwerschke, W., Mazurek, S., Stockl, P., Hutter, E., Eigenbrodt, E., and Jansen-Durr, P. (2003) Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence. Biochem J 376, 403-411. 85. Eagle, H., and Habel, K. (1956) The nutritional requirements for the propagation of poliomyelitis virus by the HeLa cell. J Exp Med 104, 271-287. 86. Claus, C., and Liebert, U. G. (2014) A renewed focus on the interplay between viruses and mitochondrial metabolism. Arch Virol 159, 1267-1277. 87. Darnell, J. E., Jr., and Eagle, H. (1958) Glucose and glutamine in poliovirus production by HeLa cells. Virology 6, 556-566. 88. Munger, J., Bennett, B. D., Parikh, A., Feng, X. J., McArdle, J., Rabitz, H. A., Shenk, T., and Rabinowitz, J. D. (2008) Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat Biotechnol 26, 1179-1186. 89. Chambers, J. W., Maguire, T. G., and Alwine, J. C. (2010) Glutamine metabolism is essential for human cytomegalovirus infection. J Virol 84, 1867-1873. 90. Chulu, J. L., Lee, L. H., Lee, Y. C., Liao, S. H., Lin, F. L., Shih, W. L., and Liu, H. J. (2007) Apoptosis induction by avian reovirus through p53 and mitochondria-mediated pathway. Biochem Biophys Res Commun 356, 529-535. 91. Hsu, C. J., Wang, C. Y., Lee, L. H., Shih, W. L., Chang, C. I., Cheng, H. L., Chulu, J. L., Ji, W. T., and Liu, H. J. (2006) Development and characterization of monoclonal antibodies against avian reovirus sigma C protein and their application in detection of avian reovirus isolates. Avian Pathol 35, 320-326. 92. Lutz, A., Dyall, J., Olivo, P. D., and Pekosz, A. (2005) Virus-inducible reporter genes as a tool for detecting and quantifying influenza A virus replication. J Virol Methods 126, 13-20. 93. Chi, P. I. (2011) ARV p17 mediates AMPK-p38 MAPK, AKT and PTEN signaling for regulating the autophagy formation that benefits for ARV replication. Master's thesis, National Pingtung University of Science and Technology, Pingtung, Taiwan 94. Chi, P. I., Huang, W. R., Lai, I. H., Cheng, C. Y., and Liu, H. J. (2013) The p17 nonstructural protein of avian reovirus triggers autophagy enhancing virus replication via activation of phosphatase and tensin deleted on chromosome 10 (PTEN) and AMP-activated protein kinase (AMPK), as well as dsRNA-dependent protein kinase (PKR)/eIF2alpha signaling pathways. J Biol Chem 288, 3571-3584. 95. Klionsky, D. J., and Emr, S. D. (2000) Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721. 96. Klionsky, D. J. (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8, 931-937. 97. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., Kominami, E., Tanaka, K., and Chiba, T. (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169, 425-434. 98. McKnight, N. C., and Zhenyu, Y. (2013) Beclin 1, an essential component and master regulator of PI3K-III in health and disease. Curr Pathobiol Rep 1, 231-238. 99. Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., and Yoshimori, T. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19, 5720-5728. 100. Tanida, I., Minematsu-Ikeguchi, N., Ueno, T., and Kominami, E. (2005) Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1, 84-91. 101. Seibenhener, M. L., Babu, J. R., Geetha, T., Wong, H. C., Krishna, N. R., and Wooten, M. W. (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24, 8055-8068. 102. Kimura, S., Noda, T., and Yoshimori, T. (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3, 452-460. 103. Gutierrez, M. G., Munafo, D. B., Beron, W., and Colombo, M. I. (2004) Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci 117, 2687-2697. 104. 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. 105. Saftig, P., Beertsen, W., and Eskelinen, E. L. (2008) LAMP-2: a control step for phagosome and autophagosome maturation. Autophagy 4, 510-512. 106. Levine, B., and Yuan, J. (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115, 2679-2688. 107. Talloczy, Z., Virgin, H. W. t., and Levine, B. (2006) PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2, 24-29. 108. Ogawa, M., Yoshimori, T., Suzuki, T., Sagara, H., Mizushima, N., and Sasakawa, C. (2005) Escape of intracellular Shigella from autophagy. Science 307, 727-731. 109. Maiuri, M. C., Zalckvar, E., Kimchi, A., and Kroemer, G. (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8, 741-752. 110. Levine, B., Sinha, S., and Kroemer, G. (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4, 600-606. 111. Djavaheri-Mergny, M., Maiuri, M. C., and Kroemer, G. (2010) Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 29, 1717-1719. 112. Lin, P. Y., Liu, H. J., Liao, M. H., Chang, C. D., Chang, C. I., Cheng, H. L., Lee, J. W., and Shih, W. L. (2010) Activation of PI 3-kinase/Akt/NF-kappaB and Stat3 signaling by avian reovirus S1133 in the early stages of infection results in an inflammatory response and delayed apoptosis. Virology 400, 104-114. 113. Pattingre, S., and Levine, B. (2006) Bcl-2 inhibition of autophagy: a new route to cancer? Cancer Res 66, 2885-2888. 114. Yamamoto, K., Ichijo, H., and Korsmeyer, S. J. (1999) BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 19, 8469-8478. 115. Talloczy, Z., Jiang, W., Virgin, H. W. t., Leib, D. A., Scheuner, D., Kaufman, R. J., Eskelinen, E. L., and Levine, B. (2002) Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc. Natl. Acad. Sci. USA 99, 190-195. 116. Sinha, S., and Levine, B. (2008) The autophagy effector Beclin 1: a novel BH3-only protein. Oncogene 27 (Suppl 1), S137-148. 117. Codogno, P., and Meijer, A. J. (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12 (Suppl 2), 1509-1518. 118. Merrick, W. C. (2004) Cap-dependent and cap-independent translation in eukaryotic systems. Gene 332, 1-11. 119. Kleijn, M., Vrins, C. L., Voorma, H. O., and Thomas, A. A. (1996) Phosphorylation state of the cap-binding protein eIF4E during viral infection. Virology 217, 486-494. 120. Perales, C., Carrasco, L., and Ventoso, I. (2003) Cleavage of eIF4G by HIV-1 protease: effects on translation. FEBS Lett 533, 89-94. 121. Ji, W. T., Wang, L., Lin, R. C., Huang, W. R., and Liu, H. J. (2009) Avian reovirus influences phosphorylation of several factors involved in host protein translation including eukaryotic translation elongation factor 2 (eEF2) in Vero cells. Biochem Biophys Res Commun 384, 301-305. 122. Jackson, W. T., Giddings, T. H., Jr., Taylor, M. P., Mulinyawe, S., Rabinovitch, M., Kopito, R. R., and Kirkegaard, K. (2005) Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol 3, e156. 123. Ji, W. T., Lee, L. H., Lin, F. L., Wang, L., and Liu, H. J. (2009) AMP-activated protein kinase facilitates avian reovirus to induce mitogen-activated protein kinase (MAPK) p38 and MAPK kinase 3/6 signalling that is beneficial for virus replication. J Gen Virol 90, 3002-3009. 124. Sir, D., Chen, W. L., Choi, J., Wakita, T., Yen, T. S., and Ou, J. H. (2008) Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology 48, 1054-1061. 125. Wirawan, E., Vande Walle, L., Kersse, K., Cornelis, S., Claerhout, S., Vanoverberghe, I., Roelandt, R., De Rycke, R., Verspurten, J., Declercq, W., Agostinis, P., Vanden Berghe, T., Lippens, S., and Vandenabeele, P. (2010) Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis 1, e18. 126. Rothman, S. (2010) How is the balance between protein synthesis and degradation achieved? Theor Biol Med Model 7, 25. 127. Guardado-Calvo, P., Vazquez-Iglesias, L., Martinez-Costas, J., Llamas-Saiz, A. L., Schoehn, G., Fox, G. C., Hermo-Parrado, X. L., Benavente, J., and van Raaij, M. J. (2008) Crystal structure of the avian reovirus inner capsid protein sigmaA. J Virol 82, 11208-11216. 128. Jacobs, B. L., Langland, J. O., and Brandt, T. (1998) Characterization of viral double-stranded RNA-binding proteins. Methods 15, 225-232. 129. Wu, X., Zhou, Y., Zhang, K., Liu, Q., and Guo, D. (2008) Isoform-specific interaction of pyruvate kinase with hepatitis C virus NS5B. FEBS Lett 582, 2155-2160. 130. Ito, K., and Suda, T. (2014) Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15, 243-256. 131. Wong, N., Ojo, D., Yan, J., and Tang, D. (2015) PKM2 contributes to cancer metabolism. Cancer Lett 356, 184-191. 132. Hartong, D. T., Dange, M., McGee, T. L., Berson, E. L., Dryja, T. P., and Colman, R. F. (2008) Novel insights into the contributions of isocitrate dehydrogenases to the Krebs cycle from patients with retinitis pigmentosa. Nat Genet 40, 1230-1234. 133. Moody, C. A., Scott, R. S., Amirghahari, N., Nathan, C. O., Young, L. S., Dawson, C. W., and Sixbey, J. W. (2005) Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A. J Virol 79, 5499-5506. 134. Mason, J. A., Davison-Versagli, C. A., Leliaert, A. K., Pape, D. J., McCallister, C., Zuo, J., Durbin, S. M., Buchheit, C. L., Zhang, S., and Schafer, Z. T. (2016) Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells. Cell Death Differ 23, 1271-1282. 135. Csibi, A., and Blenis, J. (2011) Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors. BMC Biol 9, 69. 136. Plaitakis, A., Kalef-Ezra, E., Kotzamani, D., Zaganas, I., and Spanaki, C. (2017) The glutamate dehydrogenase pathway and its roles in cell and tissue biology in health and disease. Biology (Basel) 6, 1-26. 137. Sanchez, E. L., Pulliam, T. H., Dimaio, T. A., Thalhofer, A. B., Delgado, T., and Lagunoff, M. (2017) Glycolysis, glutaminolysis, and fatty acid synthesis are required for distinct stages of Kaposi's sarcoma-associated herpesvirus lytic replication. J Virol 91, 1-15. 138. Chang, C. W., Li, H. C., Hsu, C. F., Chang, C. Y., and Lo, S. Y. (2009) Increased ATP generation in the host cell is required for efficient vaccinia virus production. J Biomed Sci 16, 80. 139. Beckes, J. D., Haller, A. A., and Perrault, J. (1987) Differential effect of ATP concentration on synthesis of vesicular stomatitis virus leader RNAs and mRNAs. J Virol 61, 3470-3478. 140. Suzuki, T. (2017) Hepatitis C virus replication. Adv Exp Med Biol 997, 199-209. 141. El-Bacha, T., Menezes, M. M., Azevedo e Silva, M. C., Sola-Penna, M., and Da Poian, A. T. (2004) Mayaro virus infection alters glucose metabolism in cultured cells through activation of the enzyme 6-phosphofructo 1-kinase. Mol Cell Biochem 266, 191-198. 142. Chuang, C., Prasanth, K. R., and Nagy, P. D. (2017) The glycolytic pyruvate kinase is recruited directly into the viral replicase complex to generate ATP for RNA synthesis. Cell Host Microbe 22, 639-652 e637. 143. Miyake, Y., Ishii, K., and Honda, A. (2017) Influenza virus infection induces host pyruvate kinase M which interacts with viral RNA-dependent RNA polymerase. Front Microbiol 8, 162. 144. Liu, F., Li, S., Liu, G., and Li, F. (2017) Triosephosphate isomerase (TPI) facilitates the replication of WSSV in Exopalaemon carinicauda. Dev Comp Immunol 71, 28-36. 145. Israelsen, W. J., and Vander Heiden, M. G. (2015) Pyruvate kinase: Function, regulation and role in cancer. Semin Cell Dev Biol 43, 43-51. 146. Gonzalez-Dosal, R., Horan, K. A., Rahbek, S. H., Ichijo, H., Chen, Z. J., Mieyal, J. J., Hartmann, R., and Paludan, S. R. (2011) HSV infection induces production of ROS, which potentiate signaling from pattern recognition receptors: role for S-glutathionylation of TRAF3 and 6. PLoS Pathog 7, e1002250. 147. Zhao, D., Xiong, Y., Lei, Q. Y., and Guan, K. L. (2013) LDH-A acetylation: implication in cancer. Oncotarget 4, 802-803. 148. Janke, R., Genzel, Y., Wetzel, M., and Reichl, U. (2011) Effect of influenza virus infection on key metabolic enzyme activities in MDCK cells. BMC Proc 5 (Suppl 8), P129. 149. Yu, Y., Clippinger, A. J., and Alwine, J. C. (2011) Viral effects on metabolism: changes in glucose and glutamine utilization during human cytomegalovirus infection. Trends Microbiol 19, 360-367. 150. Wang, G. L., Jiang, B. H., Rue, E. A., and Semenza, G. L. (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 92, 5510-5514. 151. Masoud, G. N., and Li, W. (2015) HIF-1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5, 378-389. 152. Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., and Abraham, R. T. (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22, 7004-7014. 153. Wakisaka, N., Kondo, S., Yoshizaki, T., Murono, S., Furukawa, M., and Pagano, J. S. (2004) Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1 alpha. Mol Cell Biol 24, 5223-5234. 154. Kong, F., You, H., Tang, R., and Zheng, K. (2017) The regulation of proteins associated with the cytoskeleton by hepatitis B virus X protein during hepatocarcinogenesis. Oncol Lett 13, 2514-2520. 155. Moin, S. M., Chandra, V., Arya, R., and Jameel, S. (2009) The hepatitis E virus ORF3 protein stabilizes HIF-1alpha and enhances HIF-1-mediated transcriptional activity through p300/CBP. Cell Microbiol 11, 1409-1421. 156. Werth, N., Beerlage, C., Rosenberger, C., Yazdi, A. S., Edelmann, M., Amr, A., Bernhardt, W., von Eiff, C., Becker, K., Schafer, A., Peschel, A., and Kempf, V. A. (2010) Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens. PLoS One 5, e11576. 157. Signorini, L., Croci, M., Boldorini, R., Varella, R. B., Elia, F., Carluccio, S., Villani, S., Bella, R., Ferrante, P., and Delbue, S. (2016) Interaction between human polyomavirus BK and hypoxia inducible factor-1 alpha. J Cell Physiol 231, 1343-1349. 158. Lilienbaum, A. (2013) Relationship between the proteasomal system and autophagy. Int. J. Biochem. Mol. Biol. 4, 1-26.
家禽里奧病毒(ARV)為里奧病毒科(Reoviridae family)之雙股RNA病毒,禽類感染可造成家禽病毒性關節炎、慢性呼吸道疾病及吸收不良症後群,導致業者之經濟損失。在我過去研究已證實家禽里奧病毒非結構性蛋白p17誘發自體吞噬作用有利於病毒複製,但其作用之機制仍不清楚。本研究證實不論感染家禽里奧病毒或直接轉染家禽里奧病毒p17基因,皆可正調控宿主細胞phosphatase and tensin homolog (PTEN) 及AMP-activated protein kinase (AMPK),進而降低mammalian target of rapamycin (mTOR)活性及增加微管相關蛋白輕鍵3-II (LC3-II) 之形成,誘發自體吞噬作用。另外,家禽里奧病毒非結構性蛋白p17亦調控PKR/eIF2α訊息傳遞途徑以促進自體吞噬作用。以shRNAs抑制LAMP2 及 Rab7a 之表現造成自體吞噬小體無法與細胞溶酶體結合,抑制病毒之複製。因此家禽里奧病毒非結構性蛋白p17促進 autophagosome 及 autolysosome 形成有利於病毒複製。
蛋白酶體為細胞主要降解蛋白質之機制之一,在細胞週期、凋亡與免疫系統皆扮演重要之角色。本實驗室過去研究發現以MG 132抑制proteasome活性,顯著減少家禽里奧病毒之複製。但作用之機制仍不清楚。本研究首次證實在感染家禽里奧病毒早期即可提升蛋白酶體結構蛋白proteasome subunit 6 (PSMB6)之表現及提升蛋白酶體之活性。抑制PSMB6之表現,顯著降低病毒力價。本研究證實家禽里奧病毒σA蛋白為主要調控此機制之病毒蛋白。σA促進PSMB6之表現進而促使rpl26及rpl27a被降解,進而抑制 mTORC2-ribosone 複合體形成,進一步抑制下游Akt及導致Beclin 1與14-3-3之結合量下降,因此促進自體吞噬小體 LC3-II 之形成。綜合以上研究證實家禽里奧病毒p17蛋白協同σA蛋白調控mTORC2及下游Akt,促進自體吞噬作用,以利病毒複製。本研究闡明家禽里奧病毒p17及σA蛋白如何調控autophagosome and autolysosome之形成以利病毒複製。
早期研究發現家禽里奧病毒會影響宿主細胞代謝相關蛋白之表現量。本研究首次證實σA透過提升isocitrate dehydrogenase [NAD] subunit beta (IDH3B)表現、glutaminolysis及活化HIF-1α 表現,進而正調控糖解作用之hexokinase、phosphofructokinase (PFK)、triose-phosphate isomerase (TPI) 及pyruvate kinase之mRNA表現。另一方面σA亦藉由抑制重要酵素lactate dehydrogenase A (LDHA)之表現,促進三羧酸循環及細胞ATP之生成。本研究更進一步發現病毒mRNA 之5端與3端非轉譯區之保守序列 (conserved region)。將此保守序列刪除,可顯著降低病毒之生合成,證實ATP生成是病毒蛋白合成不可或缺之因子。縱合上述結果證實家禽里奧病毒藉由影響細胞內回收系統之自體吞噬、蛋白酶體與ATP生成,提供細胞內蛋白生合成所需之能量及環境,以利病毒本身之複製。

Avian reoviruses (ARVs) are dsRNA viruses and members of the Orthoreovirus genus. ARV causes viral arthritis, chronic respiratory disease, and malabsorption syndrome, leading to a considerable economic loss to the poultry industry. My Master's study has demonstrated that ARV triggers autophagy to facilitate its replication, and the nonstructural protein p17 plays an important role in this regulation. However, the detailed mechanism of how ARV activates autophagy remain unclear. In the present study, I have uncovered that p17 activates PTEN to negatively regulate Akt. Accompanied with activation of AMPK, p17 suppresses mammalian target of rapamycin complex 1 (mTORC1) to increase the formation of LC3-II. Together with the regulation of the PKR/eIF2α pathway, this work discovers that p17 activates three distinct pathways to trigger autophagy. Furthermore, I have found that disruption of autophagosome-lysosome fusion with shRNAs targeting LAMP2 or Rab7a led to an inhibition of viral protein synthesis and virus yield, suggesting that autolysosome formation is essential during virus life cycle. An earlier study by our laboratory has demonstrated that inhibition of proteasome with MG132 results in a reduction of virus yield. However, the underlying mechanism remains unknown. In this work, I have discovered that the structural protein σA of ARV upregulates PSMB6, a subunit of proteasome and proteasome activity, which in turn promotes degradation of both rpl26 and rpl27a, thereby inhibiting mTORC2-ribosome association. This further inhibits Akt and dissociates 14-3-3 and Beclin 1, leading to enhanced autophagosome formation. Additionally, the past and present studies revealed that p17 and σA cooperate to suppress mTORC2 and Akt for triggering autophagy, thus benefiting the virus replication. Collectively, these findings provide mechanistic insights into how the p17 and σA proteins of ARV induce autophagosome and autolysosome formation to benefit virus replication.
Moreover, we demonstrated that σA is involved in the regulation of cellular metabolism which is critical for virus replication. σA triggers IDH3B and glutaminolysis, which in turn activate HIF-1α to enhance several key enzymes in the glycolysis. Together with LDHA inhibition, σA enhances the TCA flux and increase the ATP formation, which is critical for viral protein synthesis. Besides, the conserved untranslated regions (UTRs) of 5'- and 3'-termini of the ARV genome segments have been identified, and deletion of these UTRs leads to a decrease in viral protein synthesis. Taken all together, this study reveals the mechanisms underlying ARV-modulated autophagy, proteasome activity and ATP formation to benefit virus replication.
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