The enteropathogenic Escherichia coli Map effector targets mitochondria to trigger calcium mobilization, ADAM10-MAP kinase signaling and host cell death

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 proposed 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, mitochondrial-associated protein (Map), stimulates the sheddase activity of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) as well as the ERK, and p38 MAPK signaling cascades. Remarkably, all these activities were dependent upon the ability of Map to target the host mitochondria. Mitochondrially-targeted Map disrupted the mitochondrial membrane potential, resulting in Ca²⁺extrusion from the mitochondria, and its enrichment in the host cell cytoplasm. We also found that Map targeted to mitochondria is important for the activation of ADAM10 sheddase activity and for triggering host cell apoptosis. Based on these findings, we propose a model whereby Map imported to mitochondria causes mitochondrial dysfunction and Ca²⁺ efflux into the host cell cytoplasm. The acute elevation of Ca²⁺ in the cytoplasm triggers the ADAM10 sheddase activity, resulting in the release of epidermal growth factors that stimulate the ERK signaling cascade. The p38 MAPK, whose activity is Ca²⁺sensitive, may also be stimulated by the mitochondrially released Ca²⁺ in response to Map mitochondrial targting. We hypothesize that Map-dependent MAPK activation, combined with Map-mediated mitochondrial dysfunction, leads to mitochondrial host cell apoptosis, potentially contributing to EPEC colonization and infection of the gut.