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Jochmann, R.* ; Thurau, M.* ; Jung, S.* ; Hofmann, C.* ; Naschberger, E.* ; Kremmer, E. ; Harrer, T.* ; Miller, M.* ; Schaft, N.* ; Stürzl, M.*

O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter.

J. Virol. 83, 3704-3718 (2009)
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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-GlcNAc-ylation 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords long terminal repeat; rna-polymerase-ii; binding protein-1 expression; synthetase gene-expression; transcription factor sp1; t-cell-activation; factor-kappa-b; glcnac transferase; endothelial-cells; dna-binding
ISSN (print) / ISBN 0022-538X
e-ISSN 1098-5514
Journal Journal of Virology
Quellenangaben Volume: 83, Issue: 8, Pages: 3704-3718 Article Number: , Supplement: ,
Publisher American Society for Microbiology (ASM)
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)