Phospholipase D1 Couples CD4 T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication

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Replication of all human viruses depends on building blocks derived from the metabolic pathways of the infected host cell. The production of progeny virions requires synthesis of viral nucleic acids from deoxyribonucleotide triphosphates (dNTPs). HIV-1 infection in resting T cells is limited, at least in part, because the levels of critical nucleotides are low. However, stimulation of T cells turns on their metabolic machinery to increase c-Myc expression and subsequent synthesis of these key components of RNA and DNA, which augments HIV-1 replication. We have identified PLD1 as a key molecular switch that couples stimulatory T cell signals to c-Myc-dependent nucleotide biosynthesis. We also found that a small molecule that inhibits PLD1 suppresses HIV-1 replication by limiting c-Myc-dependent effects of T cell activation that support efficient HIV reverse transcription. Our study provides insight into a novel way of targeting T cell activation-induced processes such as nucleotide biosynthesis that has potential to augment current therapeutics for HIV-1.

Vyšlo v časopise: Phospholipase D1 Couples CD4 T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004864
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004864

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Zdroje

1. Pan X, Baldauf HM, Keppler OT, Fackler OT (2013) Restrictions to HIV-1 replication in resting CD4+ T lymphocytes. Cell Res 23 : 876–885. doi: 10.1038/cr.2013.74 23732522

2. Korin YD, Zack JA (1999) Nonproductive human immunodeficiency virus type 1 infection in nucleoside-treated G0 lymphocytes. J Virol 73 : 6526–6532. 10400748

3. Plesa G, Dai J, Baytop C, Riley JL, June CH, et al. (2007) Addition of deoxynucleosides enhances human immunodeficiency virus type 1 integration and 2LTR formation in resting CD4+ T cells. J Virol 81 : 13938–13942. 17928354

4. Lori F, Malykh A, Cara A, Sun D, Weinstein JN, et al. (1994) Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science 266 : 801–805. 7973634

5. Gao WY, Cara A, Gallo RC, Lori F (1993) Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication. Proc Natl Acad Sci U S A 90 : 8925–8928. 7692440

6. Lisziewicz J, Foli A, Wainberg M, Lori F (2003) Hydroxyurea in the treatment of HIV infection: clinical efficacy and safety concerns. Drug Saf 26 : 605–624. 12814330

7. Gerriets VA, Rathmell JC (2012) Metabolic pathways in T cell fate and function. Trends Immunol 33 : 168–173. doi: 10.1016/j.it.2012.01.010 22342741

8. Hollenbaugh JA, Munger J, Kim B (2011) Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS/MS analysis. Virology 415 : 153–159. doi: 10.1016/j.virol.2011.04.007 21565377

9. Loisel-Meyer S, Swainson L, Craveiro M, Oburoglu L, Mongellaz C, et al. (2012) Glut1-mediated glucose transport regulates HIV infection. Proc Natl Acad Sci U S A 109 : 2549–2554. doi: 10.1073/pnas.1121427109 22308487

10. Liu YC, Li F, Handler J, Huang CR, Xiang Y, et al. (2008) Global regulation of nucleotide biosynthetic genes by c-Myc. PLoS One 3: e2722. doi: 10.1371/journal.pone.0002722 18628958

11. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, et al. (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35 : 871–882. doi: 10.1016/j.immuni.2011.09.021 22195744

12. Sun Y, Clark EA (1999) Expression of the c-myc proto-oncogene is essential for HIV-1 infection in activated T cells. J Exp Med 189 : 1391–1398. 10224279

13. Mettling C, Desmetz C, Fiser AL, Reant B, Corbeau P, et al. (2008) Galphai protein-dependant extracellular signal-regulated kinase-1/2 activation is required for HIV-1 reverse transcription. AIDS 22 : 1569–1576. doi: 10.1097/QAD.0b013e32830abdaf 18670215

14. Popik W, Pitha PM (2000) Inhibition of CD3/CD28-mediated activation of the MEK/ERK signaling pathway represses replication of X4 but not R5 human immunodeficiency virus type 1 in peripheral blood CD4(+) T lymphocytes. J Virol 74 : 2558–2566. 10684270

15. Reid PA, Gardner SD, Williams DM, Harnett MM (1997) The antigen receptors on mature and immature T lymphocytes are coupled to phosphatidylcholine-specific phospholipase D activation. Immunology 90 : 250–256. 9135554

16. Bruntz RC, Lindsley CW, Brown HA (2014) Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer. Pharmacol Rev 66 : 1033–1079. doi: 10.1124/pr.114.009217 25244928

17. Kang DW, Park MH, Lee YJ, Kim HS, Lindsley CW, et al. (2011) Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells. Int J Cancer 128 : 805–816. doi: 10.1002/ijc.25402 20473892

18. Moolenaar WH, Kruijer W, Tilly BC, Verlaan I, Bierman AJ, et al. (1986) Growth factor-like action of phosphatidic acid. Nature 323 : 171–173. 3748188

19. Mor A, Wynne JP, Ahearn IM, Dustin ML, Du G, et al. (2009) Phospholipase D1 regulates lymphocyte adhesion via upregulation of Rap1 at the plasma membrane. Mol Cell Biol 29 : 3297–3306. doi: 10.1128/MCB.00366-09 19332557

20. Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, et al. (2009) Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nat Chem Biol 5 : 108–117. doi: 10.1038/nchembio.140 19136975

21. Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, et al. (2007) RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282 : 14056–14064. 17360704

22. Bush A, Mateyak M, Dugan K, Obaya A, Adachi S, et al. (1998) c-myc null cells misregulate cad and gadd45 but not other proposed c-Myc targets. Genes Dev 12 : 3797–3802. 9869632

23. Huang MJ, Cheng YC, Liu CR, Lin S, Liu HE (2006) A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia. Exp Hematol 34 : 1480–1489. 17046567

24. Kang DW, Min G, Park do Y, Hong KW, Min do S (2010) Rebamipide-induced downregulation of phospholipase D inhibits inflammation and proliferation in gastric cancer cells. Exp Mol Med 42 : 555–564. 20625243

25. Mantei A, Rutz S, Janke M, Kirchhoff D, Jung U, et al. (2008) siRNA stabilization prolongs gene knockdown in primary T lymphocytes. Eur J Immunol 38 : 2616–2625. doi: 10.1002/eji.200738075 18792414

26. Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, et al. (2008) Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 180 : 4476–4486. 18354169

27. Singh N, Seki Y, Takami M, Baban B, Chandler PR, et al. (2006) Enrichment of regulatory CD4(+)CD25(+) T cells by inhibition of phospholipase D signaling. Nat Methods 3 : 629–636. 16862138

28. Palmer CS, Ostrowski M, Gouillou M, Tsai L, Yu D, et al. (2014) Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection. AIDS 28 : 297–309. doi: 10.1097/QAD.0000000000000128 24335483

29. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, et al. (2013) Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14 : 500–508. doi: 10.1038/ni.2556 23525088

30. Zhang M, Wang J, Yao R, Wang L (2013) Small interfering RNA (siRNA)-mediated silencing of the M2 subunit of ribonucleotide reductase: a novel therapeutic strategy in ovarian cancer. Int J Gynecol Cancer 23 : 659–666. doi: 10.1097/IGC.0b013e318287e2b3 23466567

31. Zheng Y, Collins SL, Lutz MA, Allen AN, Kole TP, et al. (2007) A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 178 : 2163–2170. 17277121

32. DeSilva DR, Jones EA, Favata MF, Jaffee BD, Magolda RL, et al. (1998) Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy. J Immunol 160 : 4175–4181. 9574517

33. Gao WY, Johns DG, Chokekuchai S, Mitsuya H (1995) Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2',3'-dideoxynucleoside activities against replication of human immunodeficiency virus. Proc Natl Acad Sci U S A 92 : 8333–8337. 7667290

34. Heredia A, Amoroso A, Davis C, Le N, Reardon E, et al. (2003) Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1. Proc Natl Acad Sci U S A 100 : 10411–10416. 12915736

35. Taylor HE, Linde ME, Khatua AK, Popik W, Hildreth JE (2011) Sterol regulatory element-binding protein 2 couples HIV-1 transcription to cholesterol homeostasis and T cell activation. J Virol 85 : 7699–7709. doi: 10.1128/JVI.00337-11 21613400

36. Cunningham JT, Moreno MV, Lodi A, Ronen SM, Ruggero D (2014) Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157 : 1088–1103. doi: 10.1016/j.cell.2014.03.052 24855946

37. Thai M, Graham NA, Braas D, Nehil M, Komisopoulou E, et al. (2014) Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication. Cell Metab 19 : 694–701. doi: 10.1016/j.cmet.2014.03.009 24703700

38. Poeschla E (2013) The importance of becoming double-stranded: Innate immunity and the kinetic model of HIV-1 central plus strand synthesis. Virology 441 : 1–11. doi: 10.1016/j.virol.2013.03.010 23561461

39. Hollenbaugh JA, Tao S, Lenzi GM, Ryu S, Kim DH, et al. (2014) dNTP pool modulation dynamics by SAMHD1 protein in monocyte-derived macrophages. Retrovirology 11 : 63. doi: 10.1186/s12977-014-0063-2 25158827

40. Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W, et al. (2012) SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med 18 : 1682–1687. doi: 10.1038/nm.2964 22972397

41. Wagner TA, McLaughlin S, Garg K, Cheung CY, Larsen BB, et al. (2014) HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345 : 570–573. doi: 10.1126/science.1256304 25011556

42. Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, et al. (2014) HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345 : 179–183. doi: 10.1126/science.1254194 24968937

43. O'Reilly MC, Scott SA, Brown KA, Oguin TH 3rd, Thomas PG, et al. (2013) Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8-Triazaspiro[4.5]decane Core: discovery of Ml298 and Ml299 that decrease invasive migration in U87-MG glioblastoma cells. J Med Chem 56 : 2695–2699. doi: 10.1021/jm301782e 23445448

44. O'Reilly MC, Scott SA, Brown HA, Lindsley CW (2014) Further evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition. Bioorg Med Chem Lett 24 : 5553–5557. doi: 10.1016/j.bmcl.2014.11.017 25466173

45. Oguin TH 3rd, Sharma S, Stuart AD, Duan S, Scott SA, et al. (2014) Phospholipase D facilitates efficient entry of influenza virus allowing escape from innate mmune inhibition. J Biol Chem.

46. Schmid I, Cole SW, Korin YD, Zack JA, Giorgi JV (2000) Detection of cell cycle subcompartments by flow cytometric estimation of DNA-RNA content in combination with dual-color immunofluorescence. Cytometry 39 : 108–116. 10679728

47. Mathews TP, Hill S, Rose KL, Ivanova PT, Lindsley CW, et al. (2015) Human Phospholipase D Activity Transiently Regulates Pyrimidine Biosynthesis in Malignant Gliomas. ACS Chem Biol.

48. Gorden DL, Myers DS, Ivanova PT, Fahy E, Maurya MR, et al. (2015) Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J Lipid Res 56 : 722–736. doi: 10.1194/jlr.P056002 25598080

49. Fromentin E, Gavegnano C, Obikhod A, Schinazi RF (2010) Simultaneous quantification of intracellular natural and antiretroviral nucleosides and nucleotides by liquid chromatography-tandem mass spectrometry. Anal Chem 82 : 1982–1989. doi: 10.1021/ac902737j 20143781