Escherichia coli interaction with human brain microvascular endothelial cells induces signal transducer and activator of transcription 3 association with the C-terminal domain of Ec-gp96, the outer membrane protein A receptor for invasion.
Escherichia coli interaction with human brain microvascular endothelial cells induces signal transducer and activator of transcription 3 association with the C-terminal domain of Ec-gp96, the outer membrane protein A receptor for invasion.
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DOI：
10.1111/j.1462-5822.2008.01214.x
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发表时间：
2008-11
影响因子：
3.4
通讯作者：
Prasadarao NV
中科院分区：
文献类型：
--
作者：
Maruvada R;Argon Y;Prasadarao NV
我们无法开发新的治疗策略来预防由大肠杆菌K1引起的脑膜炎，这归因于我们对这种疾病的病理生理学的不完全理解。在此之前，我们已经证明了大肠杆菌外膜蛋白A与人脑微血管内皮细胞(HBMEC)上的gp96同源物EC-gp96相互作用进行侵袭。然而，EC-gp96介导的允许大肠杆菌内化的信号事件尚不完全清楚。在这里，我们证明了信号转导和转录激活因子3(STAT3)的激活及其与EC-gp96的相互作用在大肠杆菌入侵过程中是至关重要的。激活的STAT3与EC-gp96共定位于肌动蛋白缩合部位，在HBMEC中高表达显性负性(DN)形式的STAT3可显著抑制细胞的侵袭。此外，C端214位氨基酸截短的EC-gp96Δ200的过表达阻止了大肠杆菌对HBMEC的侵袭。相反，gp96缺乏与ATP的结合并没有影响侵袭。DN型磷脂酰肌醇-3激酶(PI3K)亚基P85或蛋白激酶C-α(PKC-α)的过表达对STAT3的激活及其与EC-gp96的关系没有影响，而过表达的DNSTAT3则使PI3K和PKC-α的激活消失。总之，我们的发现确认了STAT3与EC-gp96的一种新的相互作用，该作用位于PI3-激酶和PKC-α激活的上游，是大肠杆菌入侵HBMEC所必需的。
Our inability to develop new therapeutic strategies to prevent meningitis due to Escherichia coli K1 is attributed to our incomplete understanding of the pathophysiology of the disease. Previously, we demonstrated that outer membrane protein A of E. coli interacts with a gp96 homologue, Ec-gp96, on human brain microvascular endothelial cells (HBMEC) for invasion. However, signalling events mediated by Ec-gp96 that allow internalization of E. coli are incompletely understood. Here, we demonstrate that signal transducer and activator of transcription 3 (Stat3) activation and its interaction with Ec-gp96 were critical for E. coli invasion. The activated Stat3 was colocalized with Ec-gp96 at the actin condensation sites, and overexpressing a dominant negative (DN) form of Stat3 in HBMEC significantly abrogated the invasion. Furthermore, overexpression of Ec-gp96Δ200, the C-terminal 214-amino-acid truncated Ec-gp96, prevented the invasion of E. coli in HBMEC. In contrast, lack of ATP binding by gp96 did not affect the invasion. Overexpression of DN forms of either phosphatidyl inositol-3 kinase (PI3-kinase) subunit p85 or protein kinase C-α (PKC-α) had no effect on the activation of Stat3 and its association with Ec-gp96, whereas overexpression of DN-Stat3 abolished the activation of both PI3-kinase and PKC-α. Together, our findings identified a novel interaction of Stat3 with Ec-gp96, upstream of PI3-kinase and PKC-α activation that is required for the invasion of E. coli into HBMEC.
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影响因子：
4.8
作者：
Debidda, M;Wang, L;Zheng, Y
通讯作者：
Zheng, Y
影响因子：
4.8
作者：
Pop, M;Aktories, K;Schmidt, G
通讯作者：
Schmidt, G
影响因子：
3.1
作者：
Prasadarao, NV;Srivastava, PK;Sukumaran, SK
通讯作者：
Sukumaran, SK
影响因子：
3.1
作者：
Prasadarao, NV
通讯作者：
Prasadarao, NV
影响因子：
3.1
作者：
Prasadarao, NV;Wass, CA;Kim, KS
通讯作者：
Kim, KS