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Molecular and Cellular Biology, March 2005, p. 1620-1633, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1620-1633.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

P. Pavan Kumar, Prabhat Kumar Purbey, Dyavar S. Ravi, Debashis Mitra, and Sanjeev Galande*

National Centre for Cell Science, Ganeshkhind, Pune, India

Received 3 August 2004/ Returned for modification 7 September 2004/ Accepted 6 December 2004

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-2R{alpha}). However, no T-cell-specific factor(s) has been directly linked with the regulation of IL-2 and IL-2R{alpha} 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-2R{alpha}, 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-2R{alpha} 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.

* Corresponding author. Mailing address: National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune 411007, India. Phone: 91-20-25690922. Fax: 91-20-25692259. E-mail: sanjeev{at}nccs.res.in.

Molecular and Cellular Biology, March 2005, p. 1620-1633, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1620-1633.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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