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Involvement of miR-196a in HIV-associated neurocognitive disorders

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Abstract

Involvement of the human immunodeficiency virus type 1 (HIV-1) trans-activator of transcription (Tat) protein in neuronal deregulation and in the development of HIV-1 associated neurocognitive disorders (HAND) has been amply explored; however the mechanisms involved remain unclear. In search for the mechanisms, we demonstrated that Tat deregulates neuronal functions through a pathway that involved p73 and p53 pathway. We showed that Tat uses microRNA-196a (miR-196a) to deregulate the p73 pathway. Further, we found that the Abelson murine leukemia (c-Abl) phosphorylates p73 on tyrosine residue 99 (Tyr-99) in Tat-treated cells. Interestingly, Tat lost its ability to promote accumulation and phosphorylation of p73 in the presence of miR-196a mimic. Interestingly, accumulation of p73 did not lead to neuronal cell death by apoptosis as obtained by cell viability assay. Western blot analysis using antibodies directed against serine residues 807 and 811 of retinoblastoma (Rb) protein was also used to validate our data regarding lack of cell death. Hyperphosphorylation of RB (S807/811) is an indication of cell neuronal viability. These results highlight the key role played by p73 and microRNA in Tat-treated neurons leading to their deregulation and it deciphers mechanistically one of the pathways used by Tat to cause neuronal dysfunction that contributes to the development of HAND.

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References

  1. Zucchini S, Pittaluga A, Brocca-Cofano E, Summa M, Fabris M, De Michele R et al (2013) Increased excitability in tat-transgenic mice: role of tat in HIV-related neurological disorders. Neurobiol Dis 55:110–119

    Article  CAS  PubMed  Google Scholar 

  2. Fitting S, Ignatowska-Jankowska BM, Bull C, Skoff RP, Lichtman AH, Wise LE et al (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443–453

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Hahn YK, Vo P, Fitting S, Block ML, Hauser KF, Knapp PE (2010) beta-Chemokine production by neural and glial progenitor cells is enhanced by HIV-1 Tat: effects on microglial migration. J Neurochem 114:97–109

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Chang JR, Mukerjee R, Bagashev A, Del Valle L, Chabrashvili T, Hawkins BJ et al (2011) HIV-1 Tat protein promotes neuronal dysfunction through disruption of microRNAs. J Biol Chem 286:41125–41134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Arese M, Ferrandi C, Primo L, Camussi G, Bussolino F (2001) HIV-1 Tat protein stimulates in vivo vascular permeability and lymphomononuclear cell recruitment. J Immunol 166:1380–1388

    Article  CAS  PubMed  Google Scholar 

  6. Rayne F, Debaisieux S, Yezid H, Lin YL, Mettling C, Konate K et al (2010) Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells. EMBO J 29:1348–1362

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Debaisieux S, Rayne F, Yezid H, Beaumelle B (2012) The ins and outs of HIV-1 Tat. Traffic 13:355–363

    Article  CAS  PubMed  Google Scholar 

  8. Tryoen-Tóth P, Chasserot-Golaz S, Tu A, Gherib P, Bader MF, Beaumelle B et al (2013) HIV-1 Tat protein inhibits neurosecretion by binding to phosphatidylinositol 4,5-bisphosphate. J Cell Sci 126:454–463

    Article  PubMed  Google Scholar 

  9. Norman JP, Perry SW, Kasischke KA, Volsky DJ, Gelbard HA (2007) HIV-1 trans activator of transcription protein elicits mitochondrial hyperpolarization and respiratory deficit, with dysregulation of complex IV and nicotinamide adenine dinucleotide homeostasis in cortical neurons. J Immunol 178:869–876

    Article  CAS  PubMed  Google Scholar 

  10. Hui L, Chen X, Haughey NJ, Geiger JD (2012) Role of endolysosomes in HIV-1 Tat-induced neurotoxicity. ASN Neuro 4:243–252

    Article  CAS  PubMed  Google Scholar 

  11. Garden GA, Guo W, Jayadev S, Tun C, Balcaitis S, Choi J et al (2004) HIV associated neurodegeneration requires p53 in neurons and microglia. FASEB J 18:1141–1143

    CAS  PubMed  Google Scholar 

  12. Mukerjee R, Deshmane SL, Fan S, Del Valle L, White MK, Khalili K et al (2008) Involvement of the p53 and p73 transcription factors in neuroAIDS. Cell Cycle 7:2682–2690

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Mukerjee R, Claudio PP, Chang JR, Del Valle L, Sawaya BE (2010) Transcriptional regulation of HIV-1 gene expression by p53. Cell Cycle 9:4569–4578

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Sabatier JM, Vives E, Mabrouk K, Benjouad A, Rochat H, Duval A et al (1991) Evidence for neurotoxic activity of tat from human immunodeficiency virus type 1. J Virol 65:961–967

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Carey AN, Liu X, Mintzopoulos D, Paris JJ, Muschamp JW, McLaughlin JP, Kaufman MJ (2013) Conditional Tat protein expression in the GT-tg bigenic mouse brain induces gray matter density reductions. Prog Neuropsychopharmacol Biol Psychiatry 43:49–54

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Li ST, Matsushita M, Moriwaki A, Saheki Y, Lu YF, Tomizawa K, Wu HY, Terada H, Matsui H (2004) HIV-1 Tat inhibits long-term potentiation and attenuates spatial learning (vol 54, pp 362, 2004). Ann Neurol 55:758

    Article  Google Scholar 

  17. Joerger AC, Rajagopalan S, Natan E, Veprintsev DB, Robinson CV, Fersht AR (2009) Structural evolution of p53, p63, and p73: implication for heterotetramer formation. Proc Nat Acad Sci USA 106:17705–17710

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Melino G, Lu X, Gasco M, Crook T, Knight RA (2003) Functional regulation of p73 and p63: development and cancer. Trends Biochem Sci 28:663–670

    Article  CAS  PubMed  Google Scholar 

  19. Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, Jacks T (2002) p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416:560–564

    Article  CAS  PubMed  Google Scholar 

  20. Rossi M, De Laurenzi V, Munarriz E, Green DR, Liu YC, Vousden KH, Cesareni G, Melino G (2005) The ubiquitin-protein ligase Itch regulates p73 stability. EMBO J 24:836–848

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Grob TJ, Novak U, Maisse C, Barcaroli D, Lüthi AU, Pirnia F et al (2001) Human Delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ 8:1213–1223

    Article  CAS  PubMed  Google Scholar 

  22. Moll UM, Slade N (2004) p63 and p73: roles in development and tumor formation. Mol Cancer Res 2:371–386

    CAS  PubMed  Google Scholar 

  23. Murray-Zmijewski F, Lane DP, Bourdon JC (2006) p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ 13:962–972

    Article  CAS  PubMed  Google Scholar 

  24. Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC (1993) Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67:277–287

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Kashanchi F, Piras G, Radonovich MF, Duvall JF, Chiang C-M, Roeder RG, Brady JN (1994) Interaction of human TFIID with the HIV-1 transactivator Tat. Nature 367:295–299

    Article  CAS  PubMed  Google Scholar 

  26. Kim BO, Liu Y, Ruan Y, Xu ZC, Schantz L, He JJ (2003) Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. Am J Pathol 162:1693–1707

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Sawaya BE, Khalili K, Mercer WE, Denisova L, Amini S (1998) Cooperative actions of HIV-1 Vpr and p53 modulate viral gene transcription. J Biol Chem 273:20052–20057

    Article  CAS  PubMed  Google Scholar 

  28. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20

    Article  CAS  PubMed  Google Scholar 

  29. Amini S, Mameli G, Del Valle L, Skowronska A, Reiss K, Gelman BB, White MK, Khalili K, Sawaya BE (2005) p73 interacts with human immunodeficiency virus type 1 Tat in astrocytic cells and prevents its acetylation on lysine 28. Mol Cell Biol 25:8126–8138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Liu J, Uematsu H, Tsuchida N, Ikeda M-A (2011) Essential role of caspase-8 in p53/p73-dependent apoptosis induced by etoposide in head and neck carcinoma cells. Mol Cancer 10:95

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Tsai KKC, Yuan ZM (2003) c-Abl stabilizes p73 by a phosphorylation-augmented interaction. Cancer Res 63:3418–3424

    CAS  PubMed  Google Scholar 

  32. Codelia VA, Cisterna M, Alvarez AR, Moreno RD (2010) p73 participates in male germ cells apoptosis induced by etoposide. Mol Hum Reprod 16:734–742

    Article  CAS  PubMed  Google Scholar 

  33. Costanzo A, Merlo P, Pediconi N, Fulco M, Sartorelli V, Cole PA et al (2002) DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol Cell 9:175–186

    Article  CAS  PubMed  Google Scholar 

  34. Zhao B, Li L, Lei Q, Guan KL (2010) The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 24:862–874

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Nagano K, Itagaki C, Izumi T, Nunomura K, Soda Y, Tani K, Takahashi N, Takenawa T, Isobe T (2006) Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase. Oncogene 25:493–502

    CAS  PubMed  Google Scholar 

  36. Logotheti S, Michalopoulos I, Sideridou M, Daskalos A, Kossida S, Spandidos DA et al (2010) Sp1 binds to the external promoter of the p73 gene and induces the expression of TAp73 gamma in lung cancer. FEBS J 277:3014–3027

    Article  CAS  PubMed  Google Scholar 

  37. Sudhakar C, Jain N, Swarup G (2008) Sp1-like sequences mediate human caspase-3 promoter activation by p73 and cisplatin. FEBS J 275:2200–2213

    Article  CAS  PubMed  Google Scholar 

  38. Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB, Herman JG (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5′ CpG island methylation. Cancer Res 59:3352–3356

    CAS  PubMed  Google Scholar 

  39. Liu K, Zhan M, Zheng P (2008) Loss of p73 expression in six non-small cell lung cancer cell lines is associated with 5′ CPG island methylation. Exp Mol Pathol 84:59–63

    Article  CAS  PubMed  Google Scholar 

  40. Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR et al (2013) Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging 34:2091–2099

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929–930

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Guo JU, Su Y, Zhong C, Ming G-I, Song H (2011) Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145:423–434

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Jin S-G, Wu X, Li AX, Pfeifer GP (2011) Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39:5015–5024

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Valinluck V, Sowers LC (2007) Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 67:946–950

    Article  CAS  PubMed  Google Scholar 

  45. Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25:2436–2452

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Bagashev A, Fan S, Mukerjee R, Claudio PP, Chabrashvili T, Leng RP, Benchimol S, Sawaya BE (2013) Cdk9 phosphorylates Pirh2 protein and prevents degradation of p53 protein. Cell Cycle 12:1569–1577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Saunders M, Eldeen MB, Del Valle L, Reiss K, Peruzzi F, Mameli G et al (2005) p73 modulates HIV-1 Tat transcriptional and apoptotic activities in human astrocytes. Apoptosis 10:1419–1431

    Article  CAS  PubMed  Google Scholar 

  48. Alvarez AR, Sandoval PC, Leal NR, Castro PU, Kosik KS (2004) Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species. Neurobiol Dis 17:326–336

    Article  CAS  PubMed  Google Scholar 

  49. Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY et al (1999) p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage (vol 399, p 814, 1999). Nature 400:792

    Article  CAS  Google Scholar 

  50. Duan M, Yao H, Hu G, Chen X, Lund AK, Buch S (2013) HIV Tat induces expression of ICAM-1 in HUVECs: implications for miR-221/-222 in HIV-associated cardiomyopathy. PLoS One 8:e60170

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Mishra R, Singh SK (2013) HIV-1 Tat C modulates expression of miRNA-101 to suppress VE-cadherin in human brain microvascular endothelial cells. J Neurosci 33:5992–6000

    Article  CAS  PubMed  Google Scholar 

  52. Zhang H-S, Chen X-Y, Wu T-C, Sang W-W, Ruan Z (2012) MiR-34a is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation through the SIRT1/NF kappa B pathway. FEBS Lett 586:4203–4207

    Article  CAS  PubMed  Google Scholar 

  53. Zhang H-S, Wu T-C, Sang W-W, Ruan Z (2012) MiR-217 is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation by down-regulation of SIRT1. Biochem Biophys Acta 1823:1017–1023

    Article  CAS  PubMed  Google Scholar 

  54. Chen X-Y, Zhang H-S, Wu T-C, Sang W-W, Ruan Z (2013) Down-regulation of NAMPT expression by miR-182 is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation. Int J Biochem Cell Biol 45:292–298

    Article  CAS  PubMed  Google Scholar 

  55. Eletto D, Russo G, Passiatore G, Del Valle L, Giordano A, Khalili K, Gualco E, Peruzzi F (2008) Inhibition of SNAP25 expression by HIV-1 Tat involves the activity of mir-128a. J Cell Physiol 216:764–770

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Hu G, Yao H, Chaudhuri AD, Duan M, Yelamanchili SV, Wen H et al (2012) Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated neuronal dysfunction. Cell Death Dis 3:381

    Article  Google Scholar 

  57. Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001) HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78:457–467

    Article  CAS  PubMed  Google Scholar 

  58. Song L, Nath A, Geiger JD, Moore A, Hochman S (2003) Human immunodeficiency virus type 1 Tat protein directly activates neuronal N-methyl-d-aspartate receptors at an allosteric zinc-sensitive site. J Neurovirol 9:399–403

    Article  CAS  PubMed  Google Scholar 

  59. Eugenin EA, King JE, Nath A, Calderon TM, Zukin RS, Bennett MV, Berman JW (2007) HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proc Natl Acad Sci USA 104:3438–3443

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Aksenov MY, Aksenova MV, Mactutus CF, Booze RM (2012) D1/NMDA receptors and concurrent methamphetamine+HIV-1 Tat neurotoxicity. J Neuroimmune Pharmacol 7:599–608

    Article  PubMed Central  PubMed  Google Scholar 

  61. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N et al (2007) Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 26:731–743

    Article  CAS  PubMed  Google Scholar 

  62. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH et al (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26:745–752

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Agostini M, Tucci P, Killick R, Candi E, Sayan BS, di Val Cervo PR et al (2011) Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets. Proc Natl Acad Sci USA 108:21093–21098

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Research reported in this publication was supported by the National Institute of Mental Health (NIMH) and the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health under award number R01MH093331, R01NS059327 and R01NS076401. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 Tat protein.

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Authors and Affiliations

  1. Molecular Studies of Neurodegenerative Diseases Lab, FELS Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, PHA # 302, 3307 North Broad Street, Philadelphia, PA, 19140, USA

    Asen Bagashev, Ruma Mukerjee, Maryline Santerre, Fabiola E. Del Carpio-Cano, Jenny Shrestha, Ying Wang & Bassel E. Sawaya

  2. Department of Anatomy and Cell Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA, 19140, USA

    Asen Bagashev & Bassel E. Sawaya

  3. Department of Cell Biology and Anatomy, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA

    Johnny J. He

  4. Department of Neurology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA, 19140, USA

    Bassel E. Sawaya

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  1. Asen Bagashev
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  2. Ruma Mukerjee
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  3. Maryline Santerre
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Correspondence to Bassel E. Sawaya.

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Bagashev, A., Mukerjee, R., Santerre, M. et al. Involvement of miR-196a in HIV-associated neurocognitive disorders. Apoptosis 19, 1202–1214 (2014). https://doi.org/10.1007/s10495-014-1003-2

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