Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4＋ T cells
2
조회
0
다운로드
3
인용
0
참고문헌
키워드
초록
The transcription repressor Bach2 has been proposed as a regulator of T cell quiescence, but the underlying mechanism is not fully understood. Given the importance of interleukin-2 in T cell activation, we investigated whether Bach2 is a component of the network of factors that regulates interleukin-2 expression. In primary and transformed CD4＋ T cells, Bach2 overexpression counteracted T cell receptor/CD28- or PMA/ ionomycin-driven induction of interleukin-2 expression, and silencing of Bach2 had the opposite effect. Luciferase and chromatin immunoprecipitation assays revealed that Bach2 binds to multiple Maf-recognition element-like sites on the interleukin-2 proximal promoter in a manner competitive with AP-1, and thereby represses AP-1-driven induction of interleukin-2 transcription. Thus, this study demonstrates that Bach2 is a direct repressor of the interleukin-2 gene in CD4＋ T cells during the immediate early phase of AP-driven activation, thereby playing an important role in the maintenance of immune quiescence in the steady state.
Abstract
The transcription repressor Bach2 has been proposed as a regulator of T cell quiescence, but the underlying mechanism is not fully understood. Given the importance of interleukin-2 in T cell activation, we investigated whether Bach2 is a component of the network of factors that regulates interleukin-2 expression. In primary and transformed CD4＋ T cells, Bach2 overexpression counteracted T cell receptor/CD28- or PMA/ ionomycin-driven induction of interleukin-2 expression, and silencing of Bach2 had the opposite effect. Luciferase and chromatin immunoprecipitation assays revealed that Bach2 binds to multiple Maf-recognition element-like sites on the interleukin-2 proximal promoter in a manner competitive with AP-1, and thereby represses AP-1-driven induction of interleukin-2 transcription. Thus, this study demonstrates that Bach2 is a direct repressor of the interleukin-2 gene in CD4＋ T cells during the immediate early phase of AP-driven activation, thereby playing an important role in the maintenance of immune quiescence in the steady state.
참고문헌 (27)
- Siegel JP, "The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities", Science, 238, pp.75~78 (1987)
- Mingari MC, "Human interleukin-2 promotes proliferation of activated B cells via surface receptors similar to those of activated T cells", Nature, 312, pp.641~643 (1984)
- Liao W, "Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages", Nat Immunol, 12, pp.551~559 (2011)
- Liao W, "Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy", Immunity, 38, pp.13~25 (2013)
- Williams TM, "Identification of a zinc finger protein that inhibits IL-2 gene expression", Science, 254, pp.1791~1794 (1991)
- Pavan Kumar P, "Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo", Mol Cell, 22, pp.231~243 (2006)
- Martins GA, "Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival", J Exp Med, 205, pp.1959~1965 (2008)
- Oyake T, "Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site", Mol Cell Biol, 16, pp.6083~6095 (1996)
- Muto A, "The transcriptional programme of antibody class switching involves the repressor Bach2", Nature, 429, pp.566~571 (2004)
- Muto A, "Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch", EMBO J, 29, pp.4048~4061 (2010)
- Roychoudhuri R, "BACH2 represses effector programs to stabilize T(reg)- mediated immune homeostasis", Nature, 498, pp.506~510 (2013)
- Tsukumo S, "Bach2 maintains T cells in a naive state by suppressing effector memory-related genes", Proc Natl Acad Sci U S A, 110, pp.10735~10740 (2013)
- Kim EH, "Bach2 regulates homeostasis of Foxp3＋ regulatory T cells and protects against fatal lung disease in mice", J Immunol, 192, pp.985~995 (2014)
- Roychoudhuri R, "BACH2 regulates CD8＋ T cell differentiation by controlling access of AP-1 factors to enhancers", Nat immunol, 17, pp.851~860 (2016)
- Muto A, "Activation of Maf", AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with promyelocytic leukemia nuclear bodies, 2002, pp.277, 20724~20733
- Lesniewski ML, "Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4＋ T cells", Leukemia, 22, pp.2201~2207 (2008)
- International Multiple Sclerosis Genetics C, "Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis", Nature, 476, pp.214~219 (2011)
- Ferreira MA, "Identification of IL6R and chromosome 11q13. 5 as risk loci for asthma", Lancet, 378, pp.1006~1014 (2011)
- Franke A, "Genomewide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci", Nat Genet, 42, pp.1118~1125 (2010)
- Cooper JD, "Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci", Nat Genet, 40, pp.1399~1401 (2008)
- Choi YB, "Lad, an adapter protein interacting with the SH2 domain of p56lck, is required for T cell activation", J Immunol, 163, pp.5242~5249 (1999)
- Chen R, "In vivo RNA interference screens identify regulators of antiviral CD4＋ and CD8＋ T cell differentiation", Immunity, 41, pp.325~338 (2014)
- 오연경, "Early Growth Response-1 Plays a Non-redundant Role in the Differentiation of B Cells into Plasma Cells", Immune Network, 15(3), pp.161~166 (2015), 대한면역학회[DOI]
- Choi YS, "LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6", Nat Immunol, 16, pp.980~990 (2015)
- 조왕식, "Interleukin 17-expressing Innate Synovial Cells Drive K", BxN Serum-induced Arthritis, 2016, pp.16(6), 366~372[DOI]
- Han-Heom Na, "SETDB1 mediated FosB expression increases the cell proliferation rate during anticancer drug therapy", BMB Reports, 49(4), pp.238~243 (2016), 생화학분자생물학회
- Jeong YS, "Integrated expression profiling and genome-wide analysis of ChREBP targets reveals the dual role for ChREBP in glucoseregulated gene expression", PloS One, 6, pp.e22544~ (2011)