KSHV is the etiologic agent of KS, the most common tumor of AIDS patients worldwide. Currently, there are no therapeutics available to directly treat latent KSHV infection. This study reveals that latent KSHV infection induces endothelial cells to become glutamine addicted, similarly to cancer cells. Extracellular glutamine is required to feed the TCA cycle through glutaminolysis, a process called anaplerosis. KSHV induces protein expression of the glutamine transporter SLC1A5 and SLC1A5 expression is required for the survival of latently infected cells. KSHV also induces the expression of the proto-oncogene Myc and its binding partner Max, as well as, the nutrient-sensing transcription factor, MondoA and its binding partner Mlx. MondoA regulates SLC1A5 and glutaminolysis during latent KSHV infection, and its expression is required for the survival of latently infected endothelial cells. These studies show that glutaminolysis and a single glutamine transporter, under the regulation of MondoA, are required for the survival of latently infected cells, providing novel druggable targets for latently infected endothelial cells. This work supports that a cancer-like metabolic signature is established by latent KSHV infection, opening the door to further therapeutic targeting specifically of KSHV latently infected cells.
Vyšlo v časopise: Latent KSHV Infected Endothelial Cells Are Glutamine Addicted and Require Glutaminolysis for Survival. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005052 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005052
1. Dourmishev LA, Dourmishev AL, Schwartz RA, Lukac DM, Palmeri D. Molecular Genetics of Kaposi ' s Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis. Microbiology and Molecular Biology Reviews. 2003;67(2):175–212. 12794189
2. Mesri Ea, Cesarman E, Boshoff C. Kaposi's sarcoma and its associated herpesvirus. Nature reviews Cancer. 2010;10(10):707–19. doi: 10.1038/nrc2888 20865011
3. Wabinga HR, Parkin DM, Wabwire-Mangen F, Mugerwa JW. Cancer in Kampala, Uganda, in 1989–91: changes in incidence in the era of AIDS. International journal of cancer Journal international du cancer. 1993;54(1):26–36. 8478145
4. Chokunonga E, Levy LM, Bassett MT, Mauchaza BG, Thomas DB, Parkin DM. Cancer incidence in the African population of Harare, Zimbabwe: second results from the cancer registry 1993–1995. International journal of cancer Journal international du cancer. 2000;85(1):54–9. 10585583
5. Lagunoff M, Bechtel J, Venetsanakos E, Roy A-m, Abbey N, Herndier B, et al. De Novo Infection and Serial Transmission of Kaposi' s Sarcoma-Associated Herpesvirus in Cultured Endothelial Cells. Journal of Virology. 2002;76(5):2440–8. 11836422
6. Zhong W, Wang H, Herndier B, Ganem D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A. 1996;93(13):6641–6. 8692871
7. Delgado T, Carroll PA, Punjabi AS, Margineantu D, Hockenbery DM. Induction of the Warburg effect by Kaposi’ s sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells. Proceedings of the National Academy of Sciences. 2010;107(23):10696–701. www.pnas.org/cgi/doi/10.1073/pnas.1004882107.
8. Delgado T, Sanchez EL, Camarda R, Lagunoff M. Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS pathogens. 2012;8(8):e1002866–e. doi: 10.1371/journal.ppat.1002866 22916018
9. Bhatt AP, Jacobs SR, Freemerman AJ, Makowski L, Rathmell JC, Dittmer DP, et al. Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(29):11818–23. doi: 10.1073/pnas.1205995109 22752304
10. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703–7. doi: 10.1016/j.cell.2008.08.021 18775299
11. Yogev O, Lagos D, Enver T, Boshoff C. Kaposi's sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells. PLoS Pathog. 2014;10(9):e1004400. doi: 10.1371/journal.ppat.1004400 25255370
12. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY). 2009;324(5930):1029–33.
13. DeBerardinis RJ, Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29(3):313–24. doi: 10.1038/onc.2009.358 19881548
14. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest. 2013;123(9):3678–84. doi: 10.1172/JCI69600 23999442
15. Eagle BYH. Nutrition Needs of Mammalian Cells in Tissue Culture. Science. 1955;122(3168):501–4. 13255879
16. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang X-Y, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proceedings of the National Academy of Sciences. 2008;105(48):18782–7.
17. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. The Journal of cell biology. 2007;178(1):93–105. 17606868
18. Carroll PA, Diolaiti D., McFerrin L., Gu H., Djukovic D., Du J., Cheng P.F., Anderson S., Ulrich M., Hurley J.B., Raftery D., Ayer D.E., Eisenman R.N.. Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis. Cancer Cell. 2015;27 : 1–15.
19. Chambers JW, Maguire TG, Alwine JC. Glutamine metabolism is essential for human cytomegalovirus infection. Journal of virology. 2010;84(4):1867–73. doi: 10.1128/JVI.02123-09 19939921
20. Fontaine KA, Camarda R, Lagunoff M. Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol. 2014;88(8):4366–74. doi: 10.1128/JVI.03134-13 24501408
21. Eagle BYH, Habel AK. The Importance of Glucose and Glutamine for the Elaboration of Poliomyditis Virus by HeLa Cell. Journal of Experimental Medicine. 1956;104(2):271–87. 13345971
22. Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. 2012;23(4):362–9. doi: 10.1016/j.semcdb.2012.02.002 22349059
23. Dang CV. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harbor perspectives in medicine. 2013;3(8).
24. Li X, Chen S, Feng J, Deng H, Sun R. Myc is required for the maintenance of Kaposi's sarcoma-associated herpesvirus latency. J Virol. 2010;84(17):8945–8. doi: 10.1128/JVI.00244-10 20573831
25. Valiya Veettil M, Dutta D, Bottero V, Bandyopadhyay C, Gjyshi O, Sharma-Walia N, et al. Glutamate secretion and metabotropic glutamate receptor 1 expression during Kaposi's sarcoma-associated herpesvirus infection promotes cell proliferation. PLoS Pathog. 2014;10(10):e1004389. doi: 10.1371/journal.ppat.1004389 25299066
26. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871–82. doi: 10.1016/j.immuni.2011.09.021 22195744
27. Diolaiti D, McFerrin L, Carroll PA, Eisenman RN. Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis. Biochim Biophys Acta. 2014.
28. Pochini L, Scalise M, Galluccio M, Indiveri C. Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health. Frontiers in chemistry. 2014;2 : 61. doi: 10.3389/fchem.2014.00061 25157349
29. Ren P, Yue M, Xiao D, Xiu R, Gan L, Liu H, et al. ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation. The Journal of pathology. 2015;235(1):90–100. doi: 10.1002/path.4429 25142020
30. Vastag L, Koyuncu E, Grady SL, Shenk TE, Rabinowitz JD. Divergent effects of human cytomegalovirus and herpes simplex virus-1 on cellular metabolism. PLoS pathogens. 2011;7(7):e1002124–e. doi: 10.1371/journal.ppat.1002124 21779165
31. Fontaine KA, Sanchez EL, Camarda R, Lagunoff M. Dengue Virus Induces and Requires Glycolysis for Optimal Replication. J Virol. 2014.
32. Munger J, Bennett BD, Parikh A, Feng X-J, McArdle J, Rabitz Ha, et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nature biotechnology. 2008;26(10):1179–86. doi: 10.1038/nbt.1500 18820684
33. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Current opinion in genetics & development. 2008;18(1):54–61.
34. Liu J, Martin HJ, Liao G, Hayward SD. The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J Virol. 2007;81(19):10451–9. 17634226
35. Venetsanakos E, Mirza A, Fanton C, Romanov SR, Tlsty T, McMahon M. Induction of tubulogenesis in telomerase-immortalized human microvascular endothelial cells by glioblastoma cells. Experimental cell research. 2002;273(1):21–33. 11795943
36. Punjabi AS, Carroll PA, Chen L, Lagunoff M. Persistent activation of STAT3 by latent Kaposi's sarcoma-associated herpesvirus infection of endothelial cells. J Virol. 2007;81(5):2449–58. 17151100
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
