Vimentin and PSF act in concert to regulate IbeA+ E. coli K1 induced activation and nuclear translocation of NF-?B in human brain endothelial cells.

ABSTRACT: IbeA-induced NF-?B signaling through its primary receptor vimentin as well as its co-receptor PSF is required for meningitic E. coli K1 penetration and leukocyte transmigration across the blood-brain barrier (BBB), which are the hallmarks of bacterial meningitis. However, it is unknown how vimentin and PSF cooperatively contribute to IbeA-induced cytoplasmic activation and nuclear translocation of NF-?B, which are required for bacteria-mediated pathogenicities.IbeA-induced E. coli K1 invasion, polymorphonuclear leukocyte (PMN) transmigration and IKK/NF-?B activation are blocked by Caffeic acid phenethyl ester (CAPE), an inhibitor of NF-?B. IKK?/? phosphorylation is blocked by ERK inhibitors. Co-immunoprecipitation analysis shows that vimentin forms a complex with I?B, NF-?B and tubulins in the resting cells. A dissociation of this complex and a simultaneous association of PSF with NF-?B could be induced by IbeA in a time-dependent manner. The head domain of vimentin is required for the complex formation. Two cytoskeletal components, vimentin filaments and microtubules, contribute to the regulation of NF-?B. SiRNA-mediated knockdown studies demonstrate that IKK?/? phosphorylation is completely abolished in HBMECs lacking vimentin and PSF. Phosphorylation of ERK and nuclear translocation of NF-?B are entirely dependent on PSF. These findings suggest that vimentin and PSF cooperatively contribute to IbeA-induced cytoplasmic activation and nuclear translocation of NF-?B activation. PSF is essential for translocation of NF-?B and ERK to the nucleus.These findings reveal previously unappreciated facets of the IbeA-binding proteins. Cooperative contributions of vimentin and PSF to IbeA-induced cytoplasmic activation and nuclear translocation of NF-?B may represent a new paradigm in pathogen-induced signal transduction and lead to the development of novel strategies for the prevention and treatment of bacterial meningitis.

SUBMITTER: Chi F 

PROVIDER: S-EPMC3334993 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature