IQGAP1 Mediates Hcp1-Promoted Escherichia coli Meningitis by Stimulating the MAPK Pathway.

Escherichia coli-induced meningitis remains a life-threatening disease despite recent advances in the field of antibiotics-based therapeutics, necessitating continued research on its pathogenesis. The current study aims to elucidate the mechanism through which hemolysin-coregulated protein 1 (Hcp1) induces the apoptosis of human brain microvascular endothelial cells (HBMEC). Co-immunoprecipitation coupled with mass ...
spectrometric (MS) characterization led to the identification of IQ motif containing GTPase activating protein 1 (IQGAP1) as a downstream target of Hcp1. IQGAP1 was found to be up-regulated by Hcp1 treatment and mediate the stimulation of HBMEC apoptosis. It was shown that Hcp1 could compete against Smurf1 for binding to IQGAP1, thereby rescuing the latter from ubiquitin-dependent degradation. Subsequent study suggested that IQGAP1 could stimulate the MAPK signaling pathway by promoting the phosphorylation of ERK1/2, an effect that was blocked by U0126, an MAPK inhibitor. Furthermore, U0126 also demonstrated therapeutic potential against E. coli meningitis in a mouse model. Taken together, our results suggested the feasibility of targeting the MAPK pathway as a putative therapeutic strategy against bacterial meningitis.
Mesh Terms:
Animals, Apoptosis, Brain, Butadienes, Cell Line, Cytokines, Disease Models, Animal, Endothelial Cells, Escherichia coli, Escherichia coli Proteins, Humans, Meningitis, Escherichia coli, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Nitriles, Phosphorylation, RNA, Small Interfering, Signal Transduction, Ubiquitin-Protein Ligases, Up-Regulation, Virulence Factors, ras GTPase-Activating Proteins
Front Cell Infect Microbiol
Date: May. 05, 2017
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