Mitochondrial Targeting of the Enteropathogenic Escherichia coli Map Triggers Calcium Mobilization, ADAM10-MAP Kinase Signaling, and Host Cell Apoptosis
Rachana Pattani Ramachandran, Chaya Spiegel, Yael Keren, Tsafi Danieli, Naomi Melamed‐Book, Ritesh Ranjan Pal, Efrat Zlotkin‐Rivkin, Ilan Rosenshine, Benjamin Aroeti
Abstract
Enteropathogenic E. coli (EPEC) is an important human diarrhea-causing bacterium. The pathogenic effects of EPEC largely depend upon its ability to inject a series of proteins, termed effectors, into the host cells. One such effector is the mitochondrion-associated protein (Map). Map has been shown to induce actin-rich projections (i.e., filopodia) on the infected cell surface and activate a Rho GTPase enzyme termed Cdc42. Nonetheless, although most injected Map localizes to host mitochondria, its functions in the mitochondria remain unknown. Here, we show that Map targeting of mitochondria stimulates the disruption of mitochondrial membrane potential to induce Ca 2+ efflux into the host cytoplasm. The efflux stimulates the activity of a protein termed ADAM10, which induces activation of a mitogen-activated protein kinase cascade leading to host cell apoptosis. As apoptosis plays a central role in host-pathogen interactions, our findings provide novel insights into the functions of mitochondrial Map in promoting the EPEC disease.