O-Linked N -Acetylglucosaminylation of Sp1 Inhibits the Human Immunodeficiency Virus Type 1 Promoter

Journal of Virology - Tập 83 Số 8 - Trang 3704-3718 - 2009
Ramona Jochmann1, Mathias Thurau1, Susan Jung2, Christian Hofmann3,4, Elisabeth Naschberger1, Elisabeth Kremmer5, Thomas Harrer3, Matthew Miller1, Niels Schaft4, Michael Stürzl1
1Division of Molecular and Experimental Surgery, Department of Surgery, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany
2Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Schlossgarten 4, 91054 Erlangen, Germany
3Department for Internal Medicine III with Institute for Clinical Immunology, University Hospital of Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany
4Department of Dermatology, RNA Group, University Hospital of Erlangen, Hartmannstrasse 14, 91052 Erlangen, Germany
5Institute of Molecular Immunology, Helmholtz Center Munich, Marchioninistrasse 25, 81377 Munich, Germany

Tóm tắt

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N -acetyl- d -glucosamine ( O -GlcNAc), we evaluated whether increased O -GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O -GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O -GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O -GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4 + T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O -GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O -GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O -GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS.

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Tài liệu tham khảo

10.1128/jvi.59.2.284-291.1986

10.1128/jvi.66.1.139-149.1992

10.1001/jama.1979.03290520022018

10.4049/jimmunol.172.11.6649

10.1074/jbc.M308254200

10.1074/jbc.M306752200

10.1111/j.1742-4658.2007.06047.x

Calman, A. F., M. P. Busch, G. N. Vyas, T. M. McHugh, D. P. Stites, and B. M. Peterlin. 1988. Transcription and replication of human immunodeficiency virus-1 in B lymphocytes in vitro. AIDS2:185-193.

10.1038/sj.gt.3300895

10.1016/j.gene.2005.01.013

10.1128/JVI.72.4.2615-2629.1998

10.1021/bi0027480

10.1006/viro.1995.1016

10.1073/pnas.97.22.12222

10.1086/317491

10.1016/0092-8674(83)90210-6

10.1111/j.1468-1293.2005.00273.x

10.1006/viro.1996.0527

10.1074/jbc.M112331200

10.1210/en.2005-0523

10.1038/sj.emboj.7601845

10.1074/jbc.M103020200

10.1074/jbc.273.6.3611

10.1016/S0003-9861(02)00578-7

10.1128/jvi.63.6.2585-2591.1989

10.1146/annurev.biochem.66.1.315

10.1128/jvi.69.11.6705-6711.1995

10.1074/jbc.M300789200

10.1016/j.addr.2007.03.021

10.1021/bi020685a

10.1016/0092-8674(88)90015-3

10.1073/pnas.86.6.1781

10.1128/JVI.01208-07

10.1016/0092-8674(87)90594-0

10.1126/science.3059495

10.1016/S0079-6603(03)01004-3

10.1074/jbc.M307332200

10.1210/endo.143.4.8756

10.1016/S0021-9258(18)82216-5

10.2337/diabetes.52.7.1695

10.1074/jbc.272.14.9308

10.1002/jcb.20926

10.1074/jbc.M111444200

10.2144/02334bm10

10.1128/jvi.63.11.4919-4924.1989

10.1074/jbc.272.14.9316

10.1074/jbc.275.15.10983

10.1016/S0002-9440(10)64452-5

10.1097/00002030-199702000-00003

10.1016/S0092-8674(00)80243-3

10.1016/S0753-3322(00)88101-9

10.1073/pnas.89.17.8150

10.1002/ijc.23764

10.1042/bj20031873

10.1042/bj3330511

10.1128/MCB.16.1.202

10.1074/jbc.M408435200

10.1128/jvi.65.3.1414-1419.1991

10.1128/mcb.14.10.6570-6583.1994

10.1002/j.1460-2075.1993.tb06029.x

10.1185/03007998009112036

10.1128/MCB.17.11.6472

Roos, M. D., W. Xie, K. Su, J. A. Clark, X. Yang, E. Chin, A. J. Paterson, and J. E. Kudlow. 1998. Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins. Proc. Assoc. Am. Physicians110:422-432.

10.1128/JVI.01716-07

10.1007/s00262-005-0098-2

10.4049/jimmunol.174.5.3087

10.1007/s00125-004-1525-1

10.1002/j.1460-2075.1990.tb08274.x

10.1128/jvi.69.10.6572-6576.1995

10.1016/S0378-1119(99)00357-1

10.1128/JVI.00629-08

10.1089/jir.2007.0086

10.1016/S0021-9258(18)83619-5

10.1074/jbc.M605064200

10.1016/S0021-9258(18)43956-7

10.1096/fj.08-107524

10.1073/pnas.111099998

10.1016/S0092-8674(02)00810-3

10.1074/jbc.M209162200

10.1016/j.bbalip.2006.04.007

10.1016/j.bbagen.2004.03.016

10.1074/jbc.M204417200

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Journal of Virology

Tập 83 Số 8

3704-3718

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