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Action by CITED2 in the Nucleus B Κ Negative Feedback Regulation of NF-κB Action by CITED2 in the Nucleus Xiwen Lou, Shaogang Sun, Wei Chen, Yi Zhou, Yuefeng Huang, Xing Liu, Yufei Shan and Chen Wang This information is current as of September 29, 2021. J Immunol 2011; 186:539-548; Prepublished online 22 November 2010; doi: 10.4049/jimmunol.1001650 http://www.jimmunol.org/content/186/1/539 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/11/22/jimmunol.100165 Material 0.DC1 References This article cites 45 articles, 19 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/186/1/539.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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Negative Feedback Regulation of NF-kB Action by CITED2 in the Nucleus Xiwen Lou, Shaogang Sun, Wei Chen, Yi Zhou, Yuefeng Huang, Xing Liu, Yufei Shan, and Chen Wang NF-kB is a family of important transcription factors that modulate immunity, development, inflammation, and cancer. The biological activity of NF-kB is subjected to various spatial and temporal regulations. Bioinformatics analysis predicts that CITED2 is topologically close to NF-kB in the protein interaction networks. In this study, we show that ectopic expression or knockdown of CITED2 attenuates or potentiates, respectively, the expression of NF-kB–responsive genes. Mechanistically, CITED2 constitutively localizes inside the nucleus and interacts specifically with the coactivator p300. This prevents p65 from binding to p300, impairs p65 acetylation, and attenuates p65 binding to its cognate promoters. Furthermore, LPS induces CITED2 expression via NF-kB in macrophages. CITED2 sensitizes cells to TNF-a–induced apoptosis. Collectively, this study identifies Downloaded from CITED2 as a novel regulator of NF-kB in the nucleus, which reveals a negative feedback mechanism for NF-kB signaling. The Journal of Immunology, 2011, 186: 539–548. uclear factor kB is an important family of transcription modulation of NF-kB action inside the nucleus has recently factors (1), including RelA (p65), RelB, C-Rel, p50 attracted much attention, revealing unexpected multilayers of tight http://www.jimmunol.org/ N (p105), and p52 (p100) (2). The p65/p50 heterodimer regulations (8, 9). For example, a dynamic equilibrium exists is the predominant form of NF-kB in most cells, and it controls a between promoter-bound and nucleoplasmic NF-kB, which ena- wide array of genes critical in the immune response and inflam- bles the cells to retune quickly its transcriptional programs mation (3). It might also play some potential roles in development according to external stimuli (10). In addition, the modification (4, 5). The aberrant action of NF-kB is causally associated with status of histones on a given promoter could define the accessi- cancer (6) and some autoimmune diseases (7). bility of the NF-kB dimers (11, 12). Furthermore, the modification The latent form of the NF-kB heterodimer is retained in the status of NF-kB per se markedly influences its transcriptional cytoplasm through binding to its inhibitor IkBa.IkBa is quickly activity (11, 13, 14). Nuclear p65 can be phosphorylated and phosphorylated, ubiquitinated, and degraded in response to a acetylated on distinct sites by different kinases and acetyl- by guest on September 29, 2021 myriad of extracellular and intracellular stimuli, such as TNF-a, transferases (15, 16). Promoter-bound NF-kB can also be ubiq- IL-1b, LPS, and so forth. This releases the NF-kB heterodimer, uitinated and degraded in certain conditions (17, 18). All of these which then translocates from cytoplasm into nucleus to mediate provide an array of delicate mechanisms for the rapid and re- the transcription of the corresponding target genes (2). The past versible integration of stress signals. two decades have witnessed the successful elucidation, at the Recently, a growing list of novel molecules has been implicated molecular and cellular levels, of the major signaling pathways in the modulation of nuclear NF-kB action via different mecha- leading to IkBa degradation and NF-kB nuclear translocation. nisms (19). For example, Akirin2 (20) and UXT (21) were re- As with any other pivotal molecules in various biological pro- cently demonstrated to function as essential coactivators in the cesses, the activity of NF-kB is controlled strictly in vivo. The NF-kB enhanceosome. Importantly, the transcriptional coactivator p300/CBP not only serves as a scaffold for the NF-kB enhan- ceosome but also directly acetylates both p65 and histones si- Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai multaneously (22). It is a great challenge to understand how these 200031, China proteins cooperate both dynamically and temporally to remodel Received for publication May 18, 2010. Accepted for publication October 20, 2010. the NF-kB enhanceosome. This work was supported by grants from the Ministry of Science and Technology of CITED2 (35 kDa), also known as MRG1 or p35srj, may function Shanghai (09XD1404800, 09ZR1436800), the National Natural Science Foundation in several biological processes. Knockout analysis demonstrated of China (30900762, 31030021), and the Ministry of Science and Technology of that CITED2 plays crucial roles in mouse embryo development. China (2007CB914504, 2010CB529703, 2011CB910900). The CITED22/2 embryos could not proceed beyond embryo- Address correspondence and reprint requests to Dr. Chen Wang and Dr. Yufei Shan, Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, genesis. Cardiac malformation, adrenal agenesis, neural crest Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue defects, and exencephaly were observed in the embryos (23–25). Yang Road, Shanghai 200031, China. E-mail addresses: [email protected] and Further studies revealed left–right patterning defects in these [email protected] embryos, especially in co-isogenic C57BL/6J backgrounds (26). The online version of this article contains supplemental material. Moreover, CITED2 could selectively maintain adult hemopoietic Abbreviations used in this paper: BD, binding domain; BMDM, bone marrow- derived macrophage; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; stem cell functions, at least in part via Ink4a/Arf and Trp53 (27). IRF3, IFN regulatory factor 3; MOI, multiplicity of infection; PD, pull-down; PI, Mechanistically, CITED2 has been suggested as a multifunc- propidium iodide; SeV, Sendai virus; shRNA, short hairpin RNA; siRNA, small in- tional transcriptional cofactor. It can bind to the LIM domain of terfering RNA. Lhx2 and stimulate the expression of the glycoprotein hormone Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 a-subunit gene (28). It can also bind TFAP2 and potentiate its www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001650 540 CITED2 NEGATIVELY REGULATES NF-kB transcription activity, which is a possible explanation for the em- RNA. The amount of transcript of the genes of interest was measured by bryo lethality of CITED22/2 mice (23). Notably, CITED2 can be real-time RT-PCR method using the StepOne real-time PCR system (Ap- a repressor of the transcription of HIF-dependent genes (29, 30). plied Biosystems, Carlsbad, CA). The primers used were as follows: A20: sense 59-GCGTTCAGGACACAGACTTG-39, antisense 59-GCAAAGCC- To our knowledge, there is no investigation concerning the CCGTTTCAACAA-39; MCP-1: sense 59-TCGCCTCCAGCATGAAAG- function of CITED2 in immunity and inflammation. Using bioin- TC-39, antisense 59-GGCATTGATTGCATCTGGC-39; IL-8: sense 59-GG- formatics analysis, we noticed that CITED2 is topologically close to CAGCCTTCCTGATTTCTG-39, antisense 59-CTTGGCAAAACTGCAC- 9 9 9 NF-kB in the protein interaction networks. In this study, we dem- CTTCA-3 ; GRO-1: sense 5 -AGGAAGCTCACTGGTGGCTG-3 , anti- sense 59-TAGGCACAATCCAGGTGGC-39; IL-2: sense 59-GTCACAAA- onstrate that CITED2 is inducible by LPS. It prevents p65 from CAGTGCACCTAC-39, antisense 59-CCCTGGGTCTTAAGTGAAAG-39; binding to p300, impairs p65 acetylation, and weakens p65 binding IL-6 (mouse): sense 59-GAGAGGAGACTTCACAGAGGATAC-39, anti- to its cognate promoters, revealing that CITED2 is a novel repressor sense 59-GTACTCCAGAAGACCAGAGG-39; IL-12b (mouse): sense 59- of nuclear NF-kB. GCAACGTTGGAAAGGAAAGA-39, antisense 59-AAAGCCAACCAAG- CAGAAGA-39; b-actin (human): sense 59-AAAGACCTGTACGCCAA’- CAC-39, antisense 59-GTCATACTCCTGCTTGCTGAT-39; b-actin (mouse): Materials and Methods sense 59-AAAGACCTCTATGCCAACAC-39, antisense 59-ATCGTACTC- Cell culture and transfection CTGCTTGCTGAT-39. HEK293T, J774, Raw264.7, and MEF cells were cultured in DMEM medium Immunoprecipitation
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