The ability of diarrheagenic bacterial pathogens, such as enteropathogenic Escherichia coli (EPEC), to modulate the activity of mitogen-activated protein kinases (MAPKs) and cell survival has been suggested to benefit bacterial colonization and infection. However, our understanding of the mechanisms by which EPEC modulate these functions is incomplete. In this study, we show that the EPEC type III secreted effector Map stimulates the sheddase activity of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and the ERK and p38 MAPK signaling cascades. Remarkably, all these activities were dependent upon the ability of Map to target host mitochondria, mainly via its mitochondrial toxicity region (MTR). Map targeting of mitochondria disrupted the mitochondrial membrane potential, causing extrusion of mitochondrial Ca²⁺ into the host cell cytoplasm. We also found that Map targeting of mitochondria is essential for triggering host cell apoptosis. Based on these findings, we propose a model whereby Map imported into mitochondria causes mitochondrial dysfunction and Ca²⁺ efflux into the host cytoplasm. Since Ca²⁺ has been reported to promote ADAM10 activation, the acute elevation of Ca²⁺ in the cytoplasm may stimulate the ADAM10 sheddase activity, resulting in the release of epidermal growth factors that stimulate the ERK signaling cascade. As p38 activity is also Ca²⁺ sensitive, elevation in cytoplasmic Ca²⁺ may independently also activate p38. We hypothesize that Map-dependent MAPK activation, combined with Map-mediated mitochondrial dysfunction, evokes mitochondrial host cell apoptosis, potentially contributing to EPEC colonization and infection of the gut.

中文翻译：

---

肠病原性大肠杆菌图的线粒体靶向触发钙动员，ADAM10-MAP激酶信号传导和宿主细胞凋亡。

腹泻性细菌病原体（如肠致病性大肠杆菌）的能力（EPEC），以调节有丝分裂原激活的蛋白激酶（MAPK）的活性和细胞存活率已被证明有利于细菌的定殖和感染。但是，我们对EPEC调节这些功能的机制的理解还不完整。在这项研究中，我们显示了EPEC III型分泌的效应子Map刺激了含有整联蛋白和金属蛋白酶结构域的蛋白10（ADAM10）的sheddase活性以及ERK和p38 MAPK信号级联反应。值得注意的是，所有这些活动都依赖于Map主要通过其线粒体毒性区域（MTR）靶向宿主线粒体的能力。靶向线粒体的地图破坏了线粒体膜电位，导致线粒体Ca ^2+的挤出进入宿主细胞质 我们还发现，针对线粒体的Map定位对于触发宿主细胞凋亡至关重要。基于这些发现，我们提出了一个模型，其中导入到线粒体中的Map导致线粒体功能障碍和Ca ²⁺外排到宿主细胞质中。由于据报道Ca ²⁺可以促进ADAM10活化，因此细胞质中Ca ²⁺的急剧升高可能会刺激ADAM10脱氢酶活性，从而导致释放表皮生长因子，从而刺激ERK信号级联反应。由于p38活性也对Ca ²⁺敏感，因此细胞质Ca ²⁺升高也可以独立激活p38。我们假设Map依赖MAPK激活，结合Map介导的线粒体功能障碍，引起线粒体宿主细胞凋亡，可能促成EPEC定居和肠道感染。