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

Abstract

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

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Correction for Kumar et al., “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”

ACKNOWLEDGMENTS

We are grateful to K. Muniyappa for critical reading of the manuscript, G. C. Mishra for support and encouragement, T. Kohwi-Shigematsu for the gift of SATB1 cDNA and antibody, K. N. Ganesh for oligonucleotide synthesis, S. Schreiber for the FLAG-HDAC1 construct, Kuan-Teh Jeang for the GST-20-72, 1-45, 30-72, and 40-72 Tat constructs, and K. McGuire for the IL-2-Luc reporter construct. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: the molecular clone NL4.3, anti-Tat antibody from B. Cullen, CEM-GFP reporter cell line from J. Corbeil, and GST-fused Tat C22G mutant from Andrew Rice. We thank N. Sonawane for technical assistance. We thank the reviewers for their valuable comments.

P. P. Kumar and P. K. Purbey are supported by fellowships from the Council of Scientific and Industrial Research, New Delhi, India. D. S. Ravi is supported by a fellowship from the University Grants Commission, New Delhi, India. This work is partly supported by grants from the Department of Biotechnology, New Delhi, India, to S.G. S. Galande is an International Senior Research Fellow of the Wellcome Trust.