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And Represses TNF Gene Expression Activating Transcription Factor-2 Histone Deacetylase 3, a Class I Histone Deacetylase, Suppresses MAPK11-Mediated Activating Transcription Factor-2 Activation and Represses TNF Gene Expression This information is current as of September 25, 2021. Ulrich Mahlknecht, Jutta Will, Audrey Varin, Dieter Hoelzer and Georges Herbein J Immunol 2004; 173:3979-3990; ; doi: 10.4049/jimmunol.173.6.3979 http://www.jimmunol.org/content/173/6/3979 Downloaded from References This article cites 45 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/173/6/3979.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Histone Deacetylase 3, a Class I Histone Deacetylase, Suppresses MAPK11-Mediated Activating Transcription Factor-2 Activation and Represses TNF Gene Expression1 Ulrich Mahlknecht,2* Jutta Will,* Audrey Varin,† Dieter Hoelzer,* and Georges Herbein2† During inflammatory events, the induction of immediate-early genes, such as TNF-␣, is regulated by signaling cascades including the JAK/STAT, NF-␬B, and the p38 MAPK pathways, which result in phosphorylation-dependent activation of transcription factors. We observed the direct interaction of histone deacetylase (HDAC) 3, a class I histone deacetylase, with MAPK11 (p38 ␤ isoform) by West-Western-based screening analysis, pull-down assay, and two-hybrid system analysis. Results further indicated that HDAC3 decreases the MAPK11 phosphorylation state and inhibits the activity of the MAPK11-dependent transcription factor, activating transcription factor-2 (ATF-2). LPS-mediated activation of ATF-2 was inhibited by HDAC3 in a time- and Downloaded from dose-dependent manner. Inhibition of HDAC3 expression by RNA interference resulted in increased ATF-2 activation in response to LPS stimulation. In agreement with decreased ATF-2 transcriptional activity by HDAC3, HDAC3-repressed TNF gene ex- pression, and TNF protein production observed in response to LPS stimulation. Therefore, our results indicate that HDAC3 interacts directly and selectively with MAPK11, represses ATF-2 transcriptional activity, and acts as a regulator of TNF gene expression in LPS-stimulated cells, especially in mononuclear phagocytes. The Journal of Immunology, 2004, 173: 3979–3990. http://www.jimmunol.org/ echanisms of transcriptional activation have received recently been identified (6). The human histone deacetylase, considerable attention in recent years; however, it is HDAC3, is a 49 kDa protein that is expressed by many different M becoming evident that transcriptional repression, cell lines and multiple normal human tissues and is located both in which may be mediated by a number of different mechanisms, is the cell nucleus and in the cytoplasm (4, 7, 8). Although the C- just as important (1). Relaxation of the chromatin fiber facilitates terminal proportion of HDAC3 contributes to the protein’s local- transcription and is regulated by two competing enzymatic activ- ization in the nucleus via a nuclear localization sequence, which is ities, histone acetyltransferases (HATs)3 and histone deacetylases sufficient for the transport of a reporter fusion protein into the (HDACs), which modify the acetylation state of histone proteins nucleus and is required for both its deacetylase and transcriptional and other promoter-bound transcription factors (2). A still growing repression activities, the central portion of the HDAC3 protein by guest on September 25, 2021 number of HDACs has been identified in various systems and possesses a nuclear export signal (8). HDAC3 preferentially model organisms (3). On the basis of their similarity to corre- deacetylates histone lysines 5 and 12 of H4 and lysine 5 of H2A sponding yeast ancestor proteins, these enzymes have been clas- (9). HDAC3 forms oligomers in vitro and in vivo and gains its sified into three distinct families of which class I HDACs enzymatic activity in association with multiprotein repressor com- (HDAC1, 2, 3, and 8) are closely related to the yeast transcrip- plexes that contain silencing mediator for retinoid and thyroid hor- tional regulator, RPD3 (4). Class II HDACs (HDAC4, 5, 6, 7, 9, mone receptors and nuclear receptor corepressors (4, 10, 11). and 10) are similar to the yeast deacetylase, Hda1p (5). Finally, a Apart from deacetylating histone proteins and its capability to alter third class of HDACs, which contains the NAD-dependent sirtuin chromosome structure, which affects transcription factor access to proteins (SIRT1-SIRT7), which are homologous to yeast SIR2, has DNA, HDAC3 has also been described to directly associate with nonhistone proteins, such as the ATP-dependent chaperone pro- tein, heat shock protein 70 (9) and with class II HDACs (7). In *Department of Hematology/Oncology, University of Frankfurt Medical Center, addition, HDAC3 has been linked with the direct suppression of Frankfurt am Main, Germany; and †Department of Virology, Franche-Comte´ Uni- versity, Besanc¸on, France the transcriptional potential of the transcription factors GATA-2, Received for publication February 17, 2004. Accepted for publication June 30, 2004. YY1, and TFII-I (12–14) and with the deacetylation of RelA, a subunit of NF-␬B, which has been reported to be exported from the The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance nucleus in an IkB␣-dependent fashion (15). HDAC3 has also been with 18 U.S.C. Section 1734 solely to indicate this fact. demonstrated to inhibit the JNK pathway via G-protein pathway 1 This work was supported by the German National Science Foundation (Deutsche suppressor 2, which is a component of the nuclear receptor co- Forschungsgemeinschaft, MA 2057/2-3), the Heinrich and Fritz Riese Foundation, the August Scheidel Foundation, and the Franche-Comte University. repressor-HDAC3 complex (16). Four MAPK subgroups have been identified in humans: ERK, 2 Address correspondence and reprint requests to Dr. Georges Herbein, Department of Virology, Franche-Comte University, 2 Place Saint-Jacques, F-25030 Besanc¸on, JNK/stress-activated protein kinases, the ERK5/big MAPK pro- France or Dr. Ulrich Mahlknecht at the current address: Medizinische Klinik und tein, and p38 MAPK. The p38 group of MAPK contains four iso- Poliklinic V, Universitatsklinicum Heidelberg, Hospitalstrasse 3, D-69115 Heidel- ␣ ␤ ␥ ␦ berg, Germany. E-mail addresses: [email protected] or Ulrich_Mahlknecht@ forms: p38 , p38 , p38 , and p38 (17). The p38 MAPK are med.uni-heidelberg.de strongly activated by cytokines, LPS, and environmental stress, but 3 Abbreviations used in this paper: HAT, histone acetyltransferase; HDAC, histone are poorly activated by growth factors and phorbol ester (17). They deacetylase; ATF-2, activating transcription factor-2; MKK, MAPK kinase; CRE, are widely expressed in many tissues and require dual phosphor- cAMP responsive element; pTNF-Luc, luciferase reporter plasmid driven by the hu- man TNF promoter; M⌽, macrophage; TSA, trichostatin A; siRNA, small interfer- ylation on threonine and tyrosine residues to become activated. ence RNA. This phosphorylation is mediated by a protein kinase cascade, Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 3980 HDAC3 INHIBITS MAPK11/ATF-2-MEDIATED SIGNALING which consists of MAPK kinases (MKKs) that include MKK3 and cultivated in RPMI 1640 supplemented with 10% FBS. Cos7 cells were MKK6 (17). MAPK11 is known to activate downstream substrates cultured in DMEM (Invitrogen Life Technologies, Carlsbad, CA) supple- like the transcription factors serum response factor accessory pro- mented with 10% FCS, 1% glutamine, and 1% penicillin/streptomycin. Primary monocyte-derived macrophages (M⌽) were prepared from the pe- tein-1a and activating transcription factor-2 (ATF-2) through phos- ripheral blood of healthy donors and were cultured in RPMI 1640 medium phorylation (18). ATF-2 is a member of the ATF-CREB family of supplemented with 10% (v/v) pooled AB human serum (Sigma-Aldrich, transcription factors, which have been implicated in cell cycle pro- Munich, Germany), as previously described (29). gression, cell differentiation, transformation, and immune response Transfection and reporter assay (19). Being a leucine zipper transcription factor, ATF-2 binds an 8-bp response element (5Ј-TGACGTCA-3Ј), while as a homo-/ To carry out transient transfections, the DNA concentration was kept con- heterodimer it associates with other members of the ATF family or stant in the different samples by using the corresponding empty vector. A total of 5 ϫ 106 cells were transfected with 5–10 ␮g of total plasmid DNA, with
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