AUTHOR=Zhao Mingna , Zhang Lingfei , Lv Shaogang , Zhang Chenzi , Wang Lin , Chen Hong , Zhou Yan , Lou Jiatao 

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 7 - 2017

YEAR=2017

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2017.00132

DOI=10.3389/fcimb.2017.00132

ISSN=2235-2988

ABSTRACT=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 targetof 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.