Helicobacter pylori activates NF-κB by inducing Ubc13-mediated ubiquitination of lysine 158 of TAK1.
Helicobacter pylori activates NF-κB by inducing Ubc13-mediated ubiquitination of lysine 158 of TAK1.
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DOI：
10.1002/jcb.24573
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发表时间：
2013-10
影响因子：
4
通讯作者：
Chen, Lin-Feng
中科院分区：
文献类型：
--
作者：
Lamb, Acacia;Chen, JinJing;Blanke, Steven R.;Chen, Lin-Feng
幽门螺杆菌毒力因子CagA靶向多种宿主蛋白来改变不同的细胞反应，包括诱导促炎细胞因子。我们之前已经证明，caga促进赖氨酸63连接的TAK1泛素化对于幽门螺杆菌诱导的NF-κB激活和促炎细胞因子的表达是必不可少的。然而，在幽门螺杆菌介导的NF-κB活化中，TAK1泛素化和活化的分子机制尚不清楚。在这里，我们发现TAK1的赖氨酸158是在幽门螺杆菌感染反应中发生赖氨酸63连锁泛素化的关键残基。赖氨酸158突变为精氨酸可阻止TAK1的泛素化，损害幽门螺杆菌诱导的TAK1和NF-κB的活化。此外，我们证明E2泛素结合酶Ubc13参与幽门螺杆菌介导的TAK1泛素化。通过显性阴性突变体或siRNA抑制Ubc13的活性，可消除caga促进和H. pylori诱导的TAK1和NF-κB激活。这些发现进一步强调了赖氨酸63连接的TAK1泛素化在幽门螺杆菌诱导的NF-κB激活和NF-κB介导的炎症反应中的重要性。
The Helicobacter pylori virulence factor CagA targets a variety of host proteins to alter different cellular responses, including the induction of pro-inflammatory cytokines. We have previously shown that CagA-facilitated lysine 63-linked ubiquitination of TAK1 is essential for the H. pylori-induced NF-κB activation and the expression of proinflammatory cytokines. However, the molecular mechanism for TAK1 ubiquitination and activation in H. pylori-mediated NF-κB activation remains elusive. Here, we identify lysine 158 of TAK1 as the key residue undergoing lysine 63-linked ubiquitination in response to H. pylori infection. Mutation of lysine 158 to arginine prevents the ubiquitination of TAK1 and impairs H. pylori-induced TAK1 and NF-κB activation. Moreover, we demonstrate that E2 ubiquitin conjugating enzyme Ubc13 is involved in H. pylori-mediated TAK1 ubiquitination. Suppressing the activity of Ubc13 by a dominant-negative mutant or siRNA abolishes CagA-facilitated and H. pylori-induced TAK1 and NF-κB activation. These findings further underscore the importance of lysine 63-linked ubiquitination of TAK1 in H. pylori-induced NF-κB activation and NF-κB-mediated inflammatory response.
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DOI：
10.1084/jem.20062694
发表时间：
2007-06-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Reiley WW;Jin W;Lee AJ;Wright A;Wu X;Tewalt EF;Leonard TO;Norbury CC;Fitzpatrick L;Zhang M;Sun SC
通讯作者：
Sun SC
影响因子：
7.7
作者：
Lamb, Acacia;Yang, Xiao-Dong;Chen, Lin-Feng
通讯作者：
Chen, Lin-Feng
影响因子：
4.8
作者：
Higashi, H;Yokoyama, K;Hatakeyama, M
通讯作者：
Hatakeyama, M
影响因子：
12.2
作者：
Lamb, Acacia;Chen, Lin-Feng
通讯作者：
Chen, Lin-Feng
影响因子：
21.3
作者：
Sorrentino, Alessandro;Thakur, Noopur;Landstroem, Marene
通讯作者：
Landstroem, Marene