1. O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter
- Author
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Mathias Thurau, Matthew Miller, Christian Hofmann, Niels Schaft, Michael Stürzl, Ramona Jochmann, Thomas Harrer, Elisabeth Naschberger, Susan Jung, and Elisabeth Kremmer
- Subjects
CD4-Positive T-Lymphocytes ,Gene Expression Regulation, Viral ,Glycosylation ,Sp1 Transcription Factor ,Immunology ,Gene Dosage ,Biology ,N-Acetylglucosaminyltransferases ,Virus Replication ,Microbiology ,Acetylglucosamine ,Cell Line ,Transcription (biology) ,Virology ,Humans ,Enhancer ,Transcription factor ,Cells, Cultured ,HIV Long Terminal Repeat ,Sp1 transcription factor ,Promoter ,Molecular biology ,Long terminal repeat ,Genome Replication and Regulation of Viral Gene Expression ,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 ,Viral replication ,Insect Science ,HIV-1 - 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.
- Published
- 2009