STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13.
STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13.
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DOI：
10.1038/ncomms6798
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发表时间：
2014-12-15
影响因子：
16.6
通讯作者：
Watowich, Stephanie S.
中科院分区：
文献类型：
--
作者：
Zhang, Huiyuan;Hu, Hongbo;Greeley, Nathaniel;Jin, Jin;Matthews, Allison J.;Ohashi, Erika;Caetano, Mauricio S.;Li, Haiyan S.;Wu, Xuefeng;Mandal, Pijus K.;McMurray, John S.;Moghaddam, Seyed Javad;Sun, Shao-Cong;Watowich, Stephanie S.
转录调节因子STAT 3抑制天然免疫细胞中NF-κB信号传导介导的促炎细胞因子产生，但其发生机制尚不清楚。在这里，我们确定STAT 3作为一个关键的负调节Ubc 13，E2泛素结合酶，促进TRAF 6 K63连接的泛素化和NF-κB激活。Ubc 13在没有STAT 3的情况下在细胞内积累。Stat 3缺陷型巨噬细胞中Ubc 13的耗竭抑制了过度的RANKL或LPS依赖性基因表达，表明Ubc 13过表达介导了STAT 3缺乏时增强的转录反应。在RANKL激活的巨噬细胞中，STAT 3受自分泌IL-6刺激，并抑制Ets-1、Set 1甲基转移酶的增加和Ube 2n（Ubc 13）启动子处组蛋白H3赖氨酸4（H3 K4 me 3）的三甲基化。这些结果描述了STAT 3作为Ube 2n的转录抑制因子的机制，从而通过调节Ubc 13丰度来调节NF-κB活性。我们的数据表明，这条通路在骨稳态和炎症抑制中起着重要作用。
The transcriptional regulator STAT3 curbs pro-inflammatory cytokine production mediated by NF-κB signaling in innate immune cells, yet the mechanism by which this occurs has been unclear. Here we identify STAT3 as a pivotal negative regulator of Ubc13, an E2 ubiquitin-conjugating enzyme that facilitates TRAF6 K63-linked ubiquitination and NF-κB activation. Ubc13 accumulates intracellularly in the absence of STAT3. Depletion of Ubc13 in Stat3-deficient macrophages subdues excessive RANKL- or LPS-dependent gene expression, indicating Ubc13 overexpression mediates enhanced transcriptional responses in the absence of STAT3. In RANKL-activated macrophages, STAT3 is stimulated by autocrine IL-6 and inhibits accrual of Ets-1, Set1 methyltransferase and trimethylation of histone H3 lysine 4 (H3K4me3) at the Ube2n (Ubc13) promoter. These results delineate a mechanism by which STAT3 operates as a transcriptional repressor on Ube2n, thus modulating NF-κB activity by regulation of Ubc13 abundance. Our data suggest this pathway plays important roles in bone homeostasis and restraint of inflammation.
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