O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter.
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.
Jochmann
Ramona
R
Division of Molecular and Experimental Surgery, Department of Surgery, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany.
Thurau
Mathias
M
Jung
Susan
S
Hofmann
Christian
C
Naschberger
Elisabeth
E
Kremmer
Elisabeth
E
Harrer
Thomas
T
Miller
Matthew
M
Schaft
Niels
N
Stürzl
Michael
M
D000117:Acetylglucosamine / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D002478:Cells, Cultured; D018628:Gene Dosage; D015967:Gene Expression Regulation, Viral; D006031:Glycosylation; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014779:Virus Replication
D016329:Sp1 Transcription Factor; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D000117:Acetylglucosamine