幽门螺杆菌通过诱导 Ubc13 介导的 TAK1 赖氨酸 158 的泛素化来激活 NF-κB。
Helicobacter pylori activates NF-κB by inducing Ubc13-mediated ubiquitination of lysine 158 of TAK1.
机构信息
Department of Biochemistry, College of Medicine, Urbana, Illinois 61801, USA.
出版信息
J Cell Biochem. 2013 Oct;114(10):2284-92. doi: 10.1002/jcb.24573.
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.
幽门螺杆菌毒力因子 CagA 靶向多种宿主蛋白，改变不同的细胞反应，包括诱导促炎细胞因子。我们之前已经表明，CagA 促进的 TAK1 赖氨酸 63 连接的泛素化对于 H. pylori 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，TAK1 泛素化和激活的分子机制在 H. pylori 介导的 NF-κB 激活中仍然难以捉摸。在这里，我们确定 TAK1 的赖氨酸 158 是对 H. pylori 感染反应中赖氨酸 63 连接的泛素化的关键残基。将赖氨酸 158 突变为精氨酸可防止 TAK1 的泛素化，并损害 H. pylori 诱导的 TAK1 和 NF-κB 激活。此外，我们证明 E2 泛素连接酶 Ubc13 参与了 H. pylori 介导的 TAK1 泛素化。通过显性负突变体或 siRNA 抑制 Ubc13 的活性可消除 CagA 促进的和 H. pylori 诱导的 TAK1 和 NF-κB 激活。这些发现进一步强调了 TAK1 赖氨酸 63 连接的泛素化在 H. pylori 诱导的 NF-κB 激活和 NF-κB 介导的炎症反应中的重要性。
Zotero 插件