Skip to main content

Advertisement

SpringerLink
Log in

YY1 and FoxD3 Regulate Antiretroviral Zinc Finger Protein OTK18 Promoter Activation Induced by HIV-1 Infection

  • Original Article
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

OTK18 is a C2H2 type zinc finger protein involved in the regulation of HIV-1 replication in human mononuclear phagocytes. Previously, we reported OTK18 expression in brain perivascular macrophages but not in microglia in HIV encephalitis brain. We have cloned the OTK18 promoter region proximal to the transcriptional start site and determined the region responsible (−884/+1) for the basal transcriptional activity in a microglia cell line. Sequential deletion mutation analyses reveal three important response elements: Yingyang-1 (YY1; −805/−777), an HIV-1 response element for promoter activation; FoxD3 (−743/−725), a negative regulatory element; and Ets response element (−725/−707), a basal transcriptional activity response element. HIV-1 infection-induced upregulation of YY1 and c-Ets-1 protein, binding to the promoter region as determined by immunoblotting and chromatin immunoprecipitation and polymerase chain reaction (PCR) assays, and induction of YY1 was also observed in virus-infected monocyte-derived macrophages. Silencing of FoxD3 and YY1 in the cell line by small interfering RNA duplexes specific to these molecules significantly up- and downregulated basal OTK18 promoter activity in FoxD3 and YY1 response element-dependent manners, respectively. On the other hand, infection of primary cultured human microglia significantly reduced YY1 expression and induced FoxD3 as determined by immunoblotting and reverse transcription real-time PCR. These data suggest that HIV-1 induces OTK18 expression through a YY1-mediated manner in human macrophages, although its gene expression is suppressed by FoxD3 upregulation and YY1 downregulation in human microglia. This mechanism may explain the perivascular macrophage-specific expression of OTK18 in HIV encephalitis brains.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abeel T, Saeys Y, Bonnet E, Rouze P, Van de Peer Y (2008) Generic eukaryotic core promoter prediction using structural features of DNA. Genome Res 18:310−323 doi:10.1101/gr.6991408

    Article  PubMed  CAS  Google Scholar 

  • Alfano M, Grivel JC, Ghezzi S, Corti D, Trimarchi M, Poli G, Margolis L (2005) Pertussis toxin B-oligomer dissociates T cell activation and HIV replication in CD4 T cells released from infected lymphoid tissue. AIDS 19:1007−1014 doi:10.1097/01.aids.0000174446.40379.3b

    Article  PubMed  CAS  Google Scholar 

  • Alter G, Suscovich TJ, Teigen N, Meier A, Streeck H, Brander C, Altfeld M (2007) Single-stranded RNA derived from HIV-1 serves as a potent activator of NK cells. J Immunol 178:7658−7666

    PubMed  CAS  Google Scholar 

  • Alvarez-Salas LM, Benitez-Hess ML, Dipaolo JA (2005) YY-1 and c-Jun transcription factors participate in the repression of the human involucrin promoter. Int J Oncol 26:259−266

    PubMed  CAS  Google Scholar 

  • Beignon AS, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh DG, Larsson M, Gorelick RJ, Lifson JD, Bhardwaj N (2005) Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 115:3265−3275 doi:10.1172/JCI26032

    Article  PubMed  CAS  Google Scholar 

  • Bjorkbacka H, Fitzgerald KA, Huet F, Li X, Gregory JA, Lee MA, Ordija CM, Dowley NE, Golenbock DT, Freeman MW (2004) The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades. Physiol Genomics 19:319−330 doi:10.1152/physiolgenomics.00128.2004

    Article  PubMed  CAS  Google Scholar 

  • Borgmann K, Gendelman HE, Ghorpade A (2005) Isolation and HIV-1 infection of primary human microglia from fetal and adult tissue. Methods Mol Biol 304:49−70

    PubMed  Google Scholar 

  • Buescher JL, Duan F, Sun J, Price RW, Ikezu T (2008) OTK18 levels in plasma and cerebrospinal fluid correlate with viral load and CD8 T-cells in normal and AIDS patients. J Neuroimmune Pharmacol 3:230–235

    Article  PubMed  Google Scholar 

  • Carlson K, Leisman G, Limoges J, Pohlman G, Horiba M, Buescher J, Gendelman H, Ikezu T (2004a) Molecular characterization of a putative anti-retroviral transcriptional factor, OTK18. J Immunol 172:381−391

    PubMed  CAS  Google Scholar 

  • Carlson KA, Limoges J, Pohlman GD, Poluektova LY, Langford D, Masliah E, Ikezu T, Gendelman HE (2004b) OTK18 expression in brain mononuclear phagocytes parallels the severity of HIV-1 encephalitis. J Neuroimmunol 150:186−198 doi:10.1016/j.jneuroim.2004.01.021

    Article  PubMed  CAS  Google Scholar 

  • Chao CC, Gekker G, Hu S, Peterson PK (1994) Human microglial cell defense against Toxoplasma gondii. The role of cytokines. J Immunol 152:1246−1252

    PubMed  CAS  Google Scholar 

  • Chung SW, Chen YH, Perrella MA (2005) Role of Ets-2 in the regulation of heme oxygenase-1 by endotoxin. J Biol Chem 280:4578−4584 doi:10.1074/jbc.M409125200

    Article  PubMed  CAS  Google Scholar 

  • Cook JA, Grey D, Burke J, Cohen MH, Gurtman AC, Richardson JL, Wilson TE, Young MA, Hessol NA (2004) Depressive symptoms and AIDS-related mortality among a multisite cohort of HIV-positive women. Am J Public Health 94:1133−1140

    Article  PubMed  Google Scholar 

  • Coull JJ, Romerio F, Sun JM, Volker JL, Galvin KM, Davie JR, Shi Y, Hansen U, Margolis DM (2000) The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J Virol 74:6790−6799 doi:10.1128/JVI.74.15.6790-6799.2000

    Article  PubMed  CAS  Google Scholar 

  • Cristillo AD, Bierer BE (2003) Regulation of CXCR4 expression in human T lymphocytes by calcium and calcineurin. Mol Immunol 40:539−553 doi:10.1016/S0161-5890(03)00169-X

    Article  PubMed  CAS  Google Scholar 

  • Dehal P, Predki P, Olsen AS, Kobayashi A, Folta P, Lucas S, Land M, Terry A, Ecale Zhou CL, Rash S, Zhang Q, Gordon L, Kim J, Elkin C, Pollard MJ, Richardson P, Rokhsar D, Uberbacher E, Hawkins T, Branscomb E, Stubbs L (2001) Human chromosome 19 and related regions in mouse: conservative and lineage-specific evolution. Science 293:104−111 doi:10.1126/science.1060310

    Article  PubMed  CAS  Google Scholar 

  • Dittmer J (2003) The biology of the Ets1 proto-oncogene. Mol Cancer 2:29 doi:10.1186/1476-4598-2-29

    Article  PubMed  Google Scholar 

  • Dottori M, Gross MK, Labosky P, Goulding M (2001) The winged-helix transcription factor Foxd3 suppresses interneuron differentiation and promotes neural crest cell fate. Development 128:4127−4138

    PubMed  CAS  Google Scholar 

  • Fouchier RA, Meyer BE, Simon JH, Fischer U, Malim MH (1997) HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J 16:4531−4539 doi:10.1093/emboj/16.15.4531

    Article  PubMed  CAS  Google Scholar 

  • Freed E, Martin M (2001) HIVs and their replication. In: Knipe D, Howley P (eds) Fields virology, 4th edn. Lippincott Williams & Wilkins, Philadelphia, p 1986−1991

    Google Scholar 

  • Gaughan DM, Hughes MD, Oleske JM, Malee K, Gore CA, Nachman S (2004) Psychiatric hospitalizations among children and youths with human immunodeficiency virus infection. Pediatrics 113:544−551 doi:10.1542/peds.113.6.e544

    Article  Google Scholar 

  • Gendelman HE, Orenstein JM, Martin MA, Ferrua C, Mitra R, Phipps T, Wahl LA, Lane HC, Fauci AS, Burke DS et al (1988) Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med 167:1428−1441 doi:10.1084/jem.167.4.1428

    Article  PubMed  CAS  Google Scholar 

  • Gordon S, Akopyan G, Garban H, Bonavida B (2006) Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 25:1125−1142 doi:10.1038/sj.onc.1209080

    Article  PubMed  CAS  Google Scholar 

  • Gorelick RJ, Henderson LE, Hanser JP, Rein A (1988) Point mutants of Moloney murine leukemia virus that fail to package viral RNA: evidence for specific RNA recognition by a “zinc finger-like” protein sequence. Proc Natl Acad Sci USA 85:8420−8424 doi:10.1073/pnas.85.22.8420

    Article  PubMed  CAS  Google Scholar 

  • Hamilton AT, Huntley S, Tran-Gyamfi M, Baggott DM, Gordon L, Stubbs L (2006) Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes. Genome Res 16:584−594 doi:10.1101/gr.4843906

    Article  PubMed  CAS  Google Scholar 

  • He G, Margolis DM (2002) Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat. Mol Cell Biol 22:2965−2973 doi:10.1128/MCB.22.9.2965-2973.2002

    Article  PubMed  CAS  Google Scholar 

  • Holness CL, Simmons DL (1993) Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81:1607−1613

    PubMed  CAS  Google Scholar 

  • Horiba M, Martinez L, Buescher JL, Sato S, Limoges J, Jiang Y, Jones C, Ikezu T (2007) OTK18, a zinc finger protein, regulates human immunodeficiency virus type I long terminal repeat through two distinct regulatory regions. J Gen Virol 88:236−241 doi:10.1099/vir.0.82066-0

    Article  PubMed  CAS  Google Scholar 

  • Janabi N, Peudenier S, Heron B, Ng KH, Tardieu M (1995) Establishment of human microglial cell lines after transfection of primary cultures of embryonic microglial cells with the SV40 large T antigen. Neurosci Lett 195:105−108 doi:10.1016/0304-3940(94)11792-H

    Article  PubMed  CAS  Google Scholar 

  • Janabi N, Di Stefano M, Wallon C, Hery C, Chiodi F, Tardieu M (1998) Induction of human immunodeficiency virus type 1 replication in human glial cells after proinflammatory cytokines stimulation: effect of IFNgamma, IL1beta, and TNFalpha on differentiation and chemokine production in glial cells. Glia 23:304−315 doi:10.1002/(SICI)1098-1136(199808)23:4<304::AID-GLIA3>3.0.CO;2-2

    Article  PubMed  CAS  Google Scholar 

  • Joo M, Wright JG, Hu NN, Sadikot RT, Park GY, Blackwell TS, Christman JW (2007) Yin Yang 1 enhances cyclooxygenase-2 gene expression in macrophages. Am J Physiol Lung Cell Mol Physiol 292:L1219−L1226 doi:10.1152/ajplung.00474.2006

    Article  PubMed  CAS  Google Scholar 

  • Kang HJ, Adams DH, Simen A, Simen BB, Rajkowska G, Stockmeier CA, Overholser JC, Meltzer HY, Jurjus GJ, Konick LC, Newton SS, Duman RS (2007) Gene expression profiling in postmortem prefrontal cortex of major depressive disorder. J Neurosci 27:13329−13340 doi:10.1523/JNEUROSCI.4083-07.2007

    Article  PubMed  CAS  Google Scholar 

  • Kang JH, Chang SY, Yeom DH, Kim SA, Um SJ, Hong KJ (2004) Weakening of the repressive YY-1 site on the thrombospondin-1 promoter via c-Jun/YY-1 interaction. Exp Mol Med 36:300−310

    PubMed  CAS  Google Scholar 

  • Katoh M (2004) Human FOX gene family. Int J Oncol 25:1495−1500, (review)

    PubMed  CAS  Google Scholar 

  • Kim JY, Gonzalez-Scarano F, Zeichner SL, Alwine JC (1993) Replication of type 1 human immunodeficiency viruses containing linker substitution mutations in the −201 to −130 region of the long terminal repeat. J Virol 67:1658−1662

    PubMed  CAS  Google Scholar 

  • Li Y, Kappes JC, Conway JA, Price RW, Shaw GM, Hahn BH (1991) Molecular characterization of human immunodeficiency virus type 1 cloned directly from uncultured human brain tissue: identification of replication-competent and -defective viral genomes. J Virol 65:3973−3985

    PubMed  CAS  Google Scholar 

  • Looman C, Abrink M, Mark C, Hellman L (2002) KRAB zinc finger proteins: an analysis of the molecular mechanisms governing their increase in numbers and complexity during evolution. Mol Biol Evol 19:2118−2130

    PubMed  CAS  Google Scholar 

  • Margolis DM, Somasundaran M, Green MR (1994) Human transcription factor YY1 represses human immunodeficiency virus type 1 transcription and virion production. J Virol 68:905−910

    PubMed  CAS  Google Scholar 

  • Meier A, Alter G, Frahm N, Sidhu H, Li B, Bagchi A, Teigen N, Streeck H, Stellbrink HJ, Hellman J, van Lunzen J, Altfeld M (2007) MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol 81:8180−8191 doi:10.1128/JVI.00421-07

    Article  PubMed  CAS  Google Scholar 

  • Misdrahi D, Vila G, Funk-Brentano I, Tardieu M, Blanche S, Mouren-Simeoni MC (2004) DSM-IV mental disorders and neurological complications in children and adolescents with human immunodeficiency virus type 1 infection (HIV-1). Eur Psychiatry 19:182−184 doi:10.1016/j.eurpsy.2003.06.009

    Article  PubMed  CAS  Google Scholar 

  • Moriuchi M, Moriuchi H (2003) YY1 transcription factor down-regulates expression of CCR5, a major coreceptor for HIV-1. J Biol Chem 278:13003−13007 doi:10.1074/jbc.M204980200

    Article  PubMed  CAS  Google Scholar 

  • Moriuchi M, Moriuchi H, Margolis DM, Fauci AS (1999) USF/c-Myc enhances, while Yin-Yang 1 suppresses, the promoter activity of CXCR4, a coreceptor for HIV-1 entry. J Immunol 162:5986−5992

    PubMed  CAS  Google Scholar 

  • Pan G, Thomson JA (2007) Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 17:42−49 doi:10.1038/sj.cr.7310125

    Article  PubMed  CAS  Google Scholar 

  • Pohl BS, Knochel W (2001) Overexpression of the transcriptional repressor FoxD3 prevents neural crest formation in Xenopus embryos. Mech Dev 103:93−106 doi:10.1016/S0925-4773(01)00334-3

    Article  PubMed  CAS  Google Scholar 

  • Reddy MA, Yang BS, Yue X, Barnett CJ, Ross IL, Sweet MJ, Hume DA, Ostrowski MC (1994) Opposing actions of c-ets/PU.1 and c-myb protooncogene products in regulating the macrophage-specific promoters of the human and mouse colony-stimulating factor-1 receptor (c-fms) genes. J Exp Med 180:2309−2319 doi:10.1084/jem.180.6.2309

    Article  PubMed  CAS  Google Scholar 

  • Romerio F, Gabriel MN, Margolis DM (1997) Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF. J Virol 71:9375−9382

    PubMed  CAS  Google Scholar 

  • Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F (2002) HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110:521−529 doi:10.1016/S0092-8674(02)00864-4

    Article  PubMed  CAS  Google Scholar 

  • Seth A, Hodge DR, Thompson DM, Robinson L, Panayiotakis A, Watson DK, Papas TS (1993) ETS family proteins activate transcription from HIV-1 long terminal repeat. AIDS Res Hum Retrovir 9:1017−1023

    PubMed  CAS  Google Scholar 

  • Shi Y, Seto E, Chang LS, Shenk T (1991) Transcriptional repression by YY1, a human GLI-Kruppel-related protein, and relief of repression by adenovirus E1A protein. Cell 67:377−388 doi:10.1016/0092-8674(91)90189-6

    Article  PubMed  CAS  Google Scholar 

  • Shi Y, Lee JS, Galvin KM (1997) Everything you have ever wanted to know about Yin Yang 1. Biochim Biophys Acta 1332:F49−F66

    PubMed  CAS  Google Scholar 

  • Shi Z, Silveira A, Patel P, Feng X (2004) YY1 is involved in RANKL-induced transcription of the tartrate-resistant acid phosphatase gene in osteoclast differentiation. Gene 343:117−126 doi:10.1016/j.gene.2004.08.009

    Article  PubMed  CAS  Google Scholar 

  • Sieweke MH, Tekotte H, Jarosch U, Graf T (1998) Cooperative interaction of ets-1 with USF-1 required for HIV-1 enhancer activity in T cells. EMBO J 17:1728−1739 doi:10.1093/emboj/17.6.1728

    Article  PubMed  CAS  Google Scholar 

  • Starace F, Bartoli L, Aloisi MS, Antinori A, Narciso P, Ippolito G, Ravasio L, Moioli MC, Vangi D, Gennero L, Coronado OV, Giacometti A, Nappa S, Perulli ML, Montesarchio V, La Gala A, Ricci F, Cristiano L, De Marco M, Izzo C, Pezzotti P, D’Arminio Monforte A (2002) Cognitive and affective disorders associated to HIV infection in the HAART era: findings from the NeuroICONA Study. Cognitive impairment and depression in HIV/AIDS. The NeuroICONA Atudy. Acta Psychiatr Scand 106:20–26 doi:10.1034/j.1600-0447.2002.02289.x

    Article  PubMed  CAS  Google Scholar 

  • Sutton J, Costa R, Klug M, Field L, Xu D, Largaespada DA, Fletcher CF, Jenkins NA, Copeland NG, Klemsz M, Hromas R (1996) Genesis, a winged helix transcriptional repressor with expression restricted to embryonic stem cells. J Biol Chem 271:23126–23133 doi:10.1074/jbc.271.38.23126

    Article  PubMed  CAS  Google Scholar 

  • Tang M, Waterman M, Yooseph S (2002) Zinc finger gene clusters and tandem gene duplication. J Comput Biol 9:429–446 doi:10.1089/10665270252935557

    Article  PubMed  CAS  Google Scholar 

  • Yao YL, Yang WM, Seto E (2001) Regulation of transcription factor YY1 by acetylation and deacetylation. Mol Cell Biol 21:5979–5991 doi:10.1128/MCB.21.17.5979-5991.2001

    Article  PubMed  CAS  Google Scholar 

  • Ylisastigui L, Kaur R, Johnson H, Volker J, He G, Hansen U, Margolis D (2005) Mitogen-activated protein kinases regulate LSF occupancy at the human immunodeficiency virus type 1 promoter. J Virol 79:5952–5962 doi:10.1128/JVI.79.10.5952-5962.2005

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank NIH AIDS Research and Reference Reagent Program for pHIV-LTR-Luc and YU2 plasmids, Byran Cullen for pHIT/G plasmid, Edward Sato for human YY1 expression plasmid, and Robert Hromas for human FoxD3 (Genesis) expression plasmid, CNND Tissue and Cell Core Facility (Li Wu and Anuja Ghorpade) for primary culture of human microglia and monocyte elutriation, Michael Jacobsen and Meg Marquardt for editorial assistance, Santi Gorantla for consultation in viral pseudotyping, and Myhanh Che for viral titration. This work is funded by National Institute of Health R01 MH072539 (TI), P01 NS043985 (TI), and NCRR P20RR15635 (TI). The authors declare no conflict of interest or financial interests in this work.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    James L. Buescher, Lindsey B. Martinez, Shinji Sato, Satoshi Okuyama & Tsuneya Ikezu

Authors
  1. James L. Buescher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lindsey B. Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shinji Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoshi Okuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsuneya Ikezu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsuneya Ikezu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buescher, J.L., Martinez, L.B., Sato, S. et al. YY1 and FoxD3 Regulate Antiretroviral Zinc Finger Protein OTK18 Promoter Activation Induced by HIV-1 Infection. J Neuroimmune Pharmacol 4, 103–115 (2009). https://doi.org/10.1007/s11481-008-9139-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-008-9139-x

Keywords

Search

Navigation