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4560.Full.Pdf HIV-1 Tat Inhibits IL-2 Gene Transcription Through Qualitative and Quantitative Alterations of the Cooperative Rel/AP1 Complex Bound to the CD28RE/AP1 This information is current as Composite Element of the IL-2 Promoter of September 29, 2021. Esther González, Carmen Punzón, Manuel González and Manuel Fresno J Immunol 2001; 166:4560-4569; ; doi: 10.4049/jimmunol.166.7.4560 Downloaded from http://www.jimmunol.org/content/166/7/4560 References This article cites 67 articles, 45 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/166/7/4560.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. 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 Promoter1 Esther Gonza´lez, Carmen Punzo´n, Manuel Gonza´lez, and Manuel Fresno2 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-␬B- nor AP1-independent binding sites. Endogenous expression of Tat induced a decrease in the amount of the specific protein complex bound to the Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2001, 166: 4560–4569. he pathogenic mechanisms underlying HIV-1 infection cesses. Thus, Tat has been involved in both apoptotic (4–6) and and disease are extremely complex, and virological as survival (7, 8) mechanisms in the alteration of T cell proliferation T well as immunological factors contribute to pathogenesis. (9) and in the aberrant expression of several cytokine genes: Among the viral factors involved in the induced immunological TNF-␣ (10), TGF-␤ (11), IL-6 (12), IL-2 (13–16), IFN-␣ (17), and by guest on September 29, 2021 dysregulation, the transactivator protein Tat has been widely stud- IL-8 (18). Many of these effects are thought to be mediated by ied (1). Tat is a small (72–101 aa) regulatory viral protein required alterations of cellular gene expression by Tat. In this regard, it has for efficient transcription and viral replication. Besides its interac- been demonstrated a direct interaction of the viral protein with tion with the RNA stem-loop structure-denominated trans activa- several transcription factors including Oct, Sp1, and NFAT (19, tion response, Tat has been shown to interact with several members 20). Besides, indirect mechanisms have been proposed to explain of the transcriptional machinery during the process of initiation and alterations of the transcriptional activity of NF-␬B (5, 21) and AP1 elongation of viral transcription. This is the case of RNA polymer- (22) transcription factors. ase II, the kinase complex P-TEFb, and the transcriptional coactiva- In the immune response, IL-2 is considered to play a pivotal tors cAMP response element binding protein binding protein role. This cytokine is strongly regulated at the level of transcrip- (CBP)3/p300 (2, 3). tion, and the regulatory sequences conferring its inducible expres- Furthermore, the presence of Tat does not only affect viral trans- ϳ Ј activation but also mediates alterations in multiple cellular pro- sion in T cells are localized in a region of 300 bp 5 of the tran- scription start site (23). Within this region, the existence of binding sites for different ubiquitous and cell-specific transcription factors Centro de Biologı´a Molecular “Severo Ochoa” Consejo Superior de Investigaciones (NF-␬B, AP1, NFAT, and Oct1, among others) has been reported Cientificas-Universidad Auto´noma de Madrid, Cantoblanco, Madrid, Spain (reviewed in Ref. 24). Many of these sites are noncanonical, Received for publication March 27, 2000. Accepted for publication January 26, 2001. differing in one or several base pairs from the corresponding The costs of publication of this article were defrayed in part by the payment of page consensus sequences and, consequently, the existence of coop- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. erative interactions between transcription factors binding to 1 This work was supported by grants from Fondo de Investigacio´n Sanitaria, Direc- adjacent sites becomes necessary to obtain an efficient transac- cio´n General de Ensen˜anza Superior e Investigacio´n Cientı´ficayTe´cnica of Spain, tivation (25). In this regard, the CD28RE/AP1 (Ϫ164/Ϫ145) Comunidad Autonoma de Madrid, Fundacio´n para la Investigacio´n y Prevencio´n del and NFAT/AP1 distal (Ϫ286/Ϫ268) sites of the human IL-2 SIDA en Espan˜a (FIPSE), and Fundacio´n Ramo´n Areces. promoter are very representative examples of these cooperative 2 Address correspondence and reprint requests to Dr. Manuel Fresno, Centro de Bio- logı´a Molecular “Severo Ochoa” (Consejo Superior de Investigaciones Cientificas- interactions between the rel and AP1 families in the former case Universidad Auto´noma), Universidad Auto´noma de Madrid, Cantoblanco, 28049 Ma- (26) and NFAT and AP1 families in the latter (27). The drid, Spain. E-mail address: [email protected] contribution of the different regulatory elements to IL-2 gene 3 Abbreviations used in this paper: CBP, cAMP response element binding protein binding protein; Io, calcium ionophore A23187; LTR, long terminal repeat; CONA, expression is controversial (28, 29), and it seems to be different conalbumin; JNK, c-Jun N-terminal kinase. in normal and Jurkat T cells (30). Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 4561 ϩ Transcriptional transactivation regulated through composite el- GAL4-c-Jun S1 S2 constructs encode the wild-type transactivation do- ements is further complicated by the interplay between these fam- main of c-jun, and this domain mutated in its phosphorylation sites (Ser 63 ilies of transcription factors. Thus, binding of NFAT proteins to and Ser 73), respectively, in frame with the GAL4 DNA binding domain ␬ (44). The pGAL4-c-rel (309–588) and pGAL4-c-rel (309–318) express a B-like sites takes place on several promoters (20, 31–33). More- chimera containing the GAL4 DNA binding domain together with the over, NF-␬B and AP1 transcription factors are regulated not only transactivation domain of c-rel or 10 aa without transactivating capacity, by transcriptional and posttransductional mechanisms, but also by respectively, and were cloned by A. Garcı´a in our laboratory (45). The the qualitative composition of the dimers. This determines the tran- pRSV-cJ-expressing c-jun was a gift from A. Mun˜oz (Instituto de Inves- tigaciones Biomedicas, Madrid, Spain) and was previously described (44) scriptional activity, the DNA sequence specificity, and the inter- and the pRc-hc-rel expression plasmid resulting from the cloning of the actions with transcriptional coactivators (34–36). cDNA of c-rel in the HindIII-XbaI restriction sites of pRcCMV (Invitro- As the Tat viral protein has been shown to affect cytokine ex- gen, San Diego, CA) was provided by N. Rice (National Cancer Institute, pression and interact with different transcription factors, we con- Frederick, MD) (45). The plasmid pEF-BOS-NFAT1 bears the gene en- sider of interest the study of how this viral protein can alter the coding the influenza virus hemagglutinin-tagged NFAT1 and was a gift from J. M. Redondo (Centro de Biologı´a Molecular, Madrid, Spain). The cooperative interactions determining the transactivation of these CMVTat was a gift from J. Alcamı´and contains full-length HIV Tat (86 composite elements. Here, we demonstrate that Jurkat cells stably aa) under control of CMV-immediate early promoter (40). The pcDNA3 expressing Tat have a drastic inhibition in CD28RE/AP1-mediated plasmid (Invitrogen) is a cloning vector containing the CMV promoter.
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