Histone Methyltransferase Ash1l Suppresses Interleukin-6 Production and Inflammatory Autoimmune Diseases by Inducing the Ubiquitin-Editing Enzyme A20
Histone Methyltransferase Ash1l Suppresses Interleukin-6 Production and Inflammatory Autoimmune Diseases by Inducing the Ubiquitin-Editing Enzyme A20
复制标题
组蛋白甲基转移酶 Ash1l 通过诱导泛素编辑酶 A20 抑制白细胞介素 6 的产生和炎症性自身免疫性疾病
DOI：
10.1016/j.immuni.2013.08.016
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发表时间：
2013-09-19
期刊：
影响因子：
32.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Xia, Meng;Liu, Juan;Cao, Xuetao
Histone modifications play important roles in multiple physiological processes by regulating gene expression. However, the roles of histone modifications in immunity remain poorly understood. Here we report that Ash1l, a H3K4 methyltransferase, suppressed interleukin-6 (IL-6), and tumor necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, protecting mice from sepsis. Ash1l-silenced mice were more susceptible to autoimmune disease as a result of enhanced IL-6 production. Ash1l enhanced A20 expression through induction of H3K4 modification at the Tnfaip3 promoter via H3K4 methyltransferase activity of Ash1l SET (Su[var]3-9, E[z] and trithorax) domain. Ash1l suppressed NF-kappa B, mitogen-activated protein kinase (MAPK) pathways, and subsequent IL-6 production via facilitating A20-mediated NF-kappa B signal modulator NEMO and transducer TRAF6 deubiquitination. Therefore, Ash1l-mediated H3K4 methylation at the Tnfaip3 promoter is required for controlling innate IL-6 production and suppressing inflammatory autoimmune diseases, providing mechanistic insight into epigenetic modulation of immune responses and inflammation.
