MKP1 Regulates the Induction of MUC5AC Mucin by Streptococcus pneumoniae Pneumolysin by Inhibiting the PAK4-JNK Signaling Pathway
MKP1 Regulates the Induction of MUC5AC Mucin by Streptococcus pneumoniae Pneumolysin by Inhibiting the PAK4-JNK Signaling Pathway
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DOI：
10.1074/jbc.m802519200
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发表时间：
2008-11-07
影响因子：
4.8
通讯作者：
Li, Jian-Dong
中科院分区：
文献类型：
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作者：
Ha, Un-Hwan;Lim, Jae Hyang;Li, Jian-Dong
呼吸道粘膜上皮细胞通过产生一系列清除分子，作为宿主抵御吸入微生物的第一道天然防线。特别是，上皮粘蛋白通过物理捕获吸入的微生物来促进粘膜纤毛清除。因此，黏液蛋白产生的上调代表了宿主对入侵微生物的重要先天防御反应。然而，过量的粘蛋白产生压倒了粘膜纤毛清除，导致粘膜防御缺陷。因此，严格调节粘蛋白的产生对于维持有益和有害结果之间的适当平衡至关重要。在多种机制中，负调节在严格调节粘蛋白的产生中起着重要作用。在这里，我们发现PAK4-JNK信号通路在肺炎链球菌溶血素诱导的MUC5AC粘蛋白转录中起负调节作用。此外，溶肺素还通过tlr4依赖的MyD88-TRAF6-ERK信号通路选择性诱导MKP1的表达，抑制PAK4-JNK信号通路，从而导致MUC5AC粘蛋白的产生上调，以维持对肺炎链球菌感染的有效粘膜保护。这些研究对气道感染性疾病发病机制中黏液蛋白过量产生的严格调控的分子机制提供了新的见解，并可能导致新的治疗策略的发展。
Mucosal epithelial cells in the respiratory tract act as the first line of host innate defense against inhaled microbes by producing a range of molecules for clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping the inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in defective mucosal defenses. Thus, tight regulation of mucin production is critical for maintaining an appropriate balance between beneficial and detrimental outcomes. Among various mechanisms, negative regulation plays an important role in tightly regulating mucin production. Here we show that the PAK4-JNK signaling pathway acted as a negative regulator for Streptococcus pneumoniae pneumolysin-induced MUC5AC mucin transcription. Moreover pneumolysin also selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK signaling pathway, which inhibited the PAK4-JNK signaling pathway, thereby leading to up-regulation of MUC5AC mucin production to maintain effective mucosal protection against S. pneumoniae infection. These studies provide novel insights into the molecular mechanisms underlying the tight regulation of mucin overproduction in the pathogenesis of airway infectious diseases and may lead to development of new therapeutic strategies.