Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5.
Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5.
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DOI：
10.1084/jem.20111569
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发表时间：
2012-02-13
期刊：
影响因子：
--
通讯作者：
López-Rodríguez C
中科院分区：
文献类型：
--
作者：
Buxadé M;Lunazzi G;Minguillón J;Iborra S;Berga-Bolaños R;Del Val M;Aramburu J;López-Rodríguez C
NFAT 5调节TLR刺激的基因的诱导，其与Tnf启动子组成性结合，而不管TLR连接和募集到Nos 2和II 6，这依赖于TLR活化和IKK b。Toll样受体（TLR）参与转录调节因子网络，以诱导抗菌免疫所必需的基因。我们报告说，NFAT 5，以前的特点是作为一个渗透压应激反应因子，调节多个TLR诱导的基因在巨噬细胞的表达独立的渗透压。NFAT 5是诱导关键的抗微生物基因Nos 2（诱导型一氧化氮合酶[iNOS]）响应于低剂量和高剂量的TLR激动剂，但所需的TNF和IL 6主要在温和的刺激条件下，表明NFAT 5可以调节特定的基因模式，这取决于病原体负荷强度。NFAT 5表现出两种与靶基因相关的模式，因为它与TNF和其他基因组成性结合，而不管TLR刺激如何，而其向Nos 2或II 6的募集需要TLR活化。进一步的分析显示TLR诱导的NFAT 5向Nos 2的募集依赖于κB激酶β抑制剂（IKK）的活性和从头蛋白合成，并且对组蛋白去乙酰化酶敏感。在体内，NFAT 5是必要的有效免疫力，对利什曼原虫，其清除需要TLR和iNOS的巨噬细胞的表达。这些发现将NFAT 5鉴定为哺乳动物抗病原体反应的新型调节剂。
NFAT5 regulates the induction of TLR-stimulated genes with constitutive binding to the Tnf promoter regardless of TLR ligation and recruitment to Nos2 and Il6 dependent on TLR activation and IKKb. Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses.
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DOI：
10.1038/nri2569
发表时间：
2009-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Geijtenbeek TB;Gringhuis SI
通讯作者：
Gringhuis SI
影响因子：
3.7
作者：
Drews-Elger K;Ortells MC;Rao A;López-Rodriguez C;Aramburu J
通讯作者：
Aramburu J
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
影响因子：
4.8
作者：
Caivano, M;Gorgoni, B;Poli, V
通讯作者：
Poli, V