HIV-1 Tat inhibits IL-2 gene transcription through qualitative and quantitative alterations of the cooperative Rel/AP1 complex bound to the CD28RE/AP1 composite element of the IL-2 promoter.
Dysregulation of cytokine secretion plays an important role in AIDS pathogenesis. Here, we demonstrate that expression of HIV-1 Tat protein in Jurkat cells induces a severe impairment of IL-2 but not TNF gene transcription. Interestingly, this inhibition correlates with the effect of the viral protein on the transactivation of the CD28RE/AP1 composite element (-164/-154), but not with that observed on the NFAT/AP1 site of the IL-2 gene promoter, neither with the effect on NF-kappa B- nor AP1-independent binding sites. Endogenous expression of Tat induced a decrease in the amount of the specific protein complex bound to the CD28RE/AP1 probe after PMA plus calcium ionophore stimulation. This effect was accompanied by qualitative alterations of the AP1 complex. Thus, in wild-type Jurkat cells, c-jun was absent from the complex, whereas in Tat-expressing cells, c-jun was increasingly recruited overtime. By contrast, similar amounts of c-rel and a small amount of NFAT1 were detected both in wild type and in Jurkat Tat(+) cells. Furthermore, Tat not only induced the participation of c-jun in the cooperative complex but also a decrease in its transactivation activity alone or in combination with c-rel. Thus, the interaction of Tat with the components of this rel/AP1 cooperative complex seems to induce quantitative and qualitative alterations of this complex as activation progresses, resulting in a decrease of IL-2 gene transcription. Altogether our results suggest the existence of tuned mechanisms that allow the viral protein to specifically affect cooperative interactions between transcription factors.
González
E
E
Centro de Biología Molecular Severo Ochoa Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
Punzón
C
C
González
M
M
Fresno
M
M
D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D015696:Gene Products, tat / Q000096:biosynthesis / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019169:Jurkat Cells / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000276:immunology*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020218:Response Elements / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D015696:Gene Products, tat; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D020569:Proto-Oncogene Proteins c-rel; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus