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NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection

Author:
Hemrajani, Cordula, Berger, Cedric N., Robinson, Keith S., Marchès, Olivier, Mousnier, Aurelie, Frankel, Gad
Source:
Proceedings of the National Academy of Sciences of the United States of America 2010 v.107 no.7 pp. 3129-3134
ISSN:
0027-8424
Subject:
Citrobacter rodentium, Shigella, amino acids, apoptosis, bacterial adhesion, brefeldin A, calcium, caspase-3, cell viability, endoplasmic reticulum, enterohemorrhagic Escherichia coli, enteropathogenic Escherichia coli, humans, mice, pathogens, signal transduction, tunicamycin, two hybrid system techniques
Abstract:
The human pathogens enteropathogenic (EPEC) and enterohemorrhagic Escherichia coli and the related mouse pathogen Citrobacter rodentium subvert a variety of host cell signaling pathways via their plethora of type III secreted effectors, including triggering of an early apoptotic response. EPEC-infected cells do not develop late apoptotic symptoms, however. In this study we demonstrate that the NleH family effectors, homologs of the Shigella effector kinase OspG, blocks apoptosis. During EPEC infection, NleH effectors inhibit elevation of cytosolic Ca²⁺ concentrations, nuclear condensation, caspase-3 activation, and membrane blebbing and promote cell survival. NleH1 alone is sufficient to prevent procaspase-3 cleavage induced by the proapoptotic compounds staurosporine, brefeldin A, and tunicamycin. Using C. rodentium, we found that NleH inhibits procaspase-3 cleavage at the bacterial attachment sites in vivo. A yeast two-hybrid screen identified the endoplasmic reticulum six-transmembrane protein Bax inhibitor-1 (BI-1) as an NleH-interacting partner. We mapped the NleH-binding site to the N-terminal 40 amino acids of BI-1. Knockdown of BI-1 resulted in the loss of NleH's antiapoptotic activity. These results indicate that NleH effectors are inhibitors of apoptosis that may act through BI-1 to carry out their cytoprotective function.
Agid:
2367812