Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells.
One hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the dysregulation of cytokine gene expression in T cells. Transfection of T cells with human T-cell leukemia type 1 or 2 transactivator results in the induction of the T-cell-restricted cytokine interleukin-2 (IL-2) and its receptor (IL-2Ralpha). However, no T-cell-specific factor(s) has been directly linked with the regulation of IL-2 and IL-2Ralpha transcription by influencing the promoter activity. Thymocytes from SATB1 (special AT-rich sequence binding protein 1) knockout mice have been shown to ectopically express IL-2Ralpha, suggesting involvement of SATB1 in its negative regulation. Here we show that SATB1, a T-cell-specific global gene regulator, binds to the promoters of human IL-2 and IL-2Ralpha and recruits histone deacetylase 1 (HDAC1) in vivo. SATB1 also interacts with Tat in HIV-1-infected T cells. The functional interaction between HIV-1 Tat and SATB1 requires its PDZ-like domain, and the binding of the HDAC1 corepressor occurs through the same. Furthermore, Tat competitively displaces HDAC1 that is bound to SATB1, leading to increased acetylation of the promoters in vivo. Transduction with SATB1 interaction-deficient soluble Tat (Tat 40-72) and reporter assays using a transactivation-negative mutant (C22G) of Tat unequivocally demonstrated that the displacement of HDAC1 itself is sufficient for derepression of these promoters in vivo. These results suggest a novel mechanism by which HIV-1 Tat might overcome SATB1-mediated repression in T cells.
Kumar
P Pavan
PP
National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune 411007, India.
Purbey
Prabhat Kumar
PK
Ravi
Dyavar S
DS
Mitra
Debashis
D
Galande
Sanjeev
S
D000107:Acetylation; D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D036961:Matrix Attachment Region Binding Proteins; D018123:Receptors, Interleukin; D012097:Repressor Proteins; C076189:SATB1 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases