title: Bacterial protein AvrA stabilizes intestinal epithelial tight junctions via blockage of the C-Jun N-terminal kinase pathway.
abstract: The Salmonella type III secretory system secretes virulence proteins, called effectors. Effectors are responsible for the alteration of tight junctions (TJ) and epithelial functions in intestinal infection and inflammation. In a previous study, we have demonstrated that a bacterial effector AvrA plays a role in stabilizing TJs and balancing the opposing action of other bacterial effectors. However, the molecular mechanisms by which AvrA-modulates TJ protein expression remain unknown. AvrA possesses acetyltransferase activity toward specific mitogen-activated protein kinase kinases (MAPKKs) and potently inhibits the c-Jun N-terminal kinase (JNK) pathway in inflammation. Inhibition of the JNK pathway is known to inhibit the TJ protein disassemble. Therefore, we hypothesize that AvrA stabilizes intestinal epithelial TJs via c-Jun and JNK pathway blockage. Using both in vitro and in vivo models, we showed that AvrA targets the c-Jun and JNK pathway that in turn stabilizes TJ protein ZO-1. Inhibition of JNK abolished the effect of AvrA on ZO-1. We further determined that AvrA suppressed the transcription factor activator protein-1, which was regulated by activated JNK. Moreover, we identified the functional domain of AvrA that directly regulated TJs using a series of AvrA mutants. The role of AvrA represents a highly refined bacterial strategy that helps the bacteria survive in the host and dampens the inflammatory response of the host. Our findings have uncovered a novel role of the bacterial protein AvrA in suppressing the inflammatory response of the host through JNK-regulated blockage of epithelial cell barrier function.
authors.affiliation: Rush University; Cohn Research Building; Chicago, IL USA.
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Rush University; Cohn Research Building; Chicago, IL USA.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Wu
authors.affiliation: Rush University; Cohn Research Building; Chicago, IL USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Biostatistics and Computational Biology; University of Rochester ; Rochester, NY USA.
authors.forename: Yinglin
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Cell and Molecular Physiology; Stritch School of Medicine ; Loyola University ; Chicago, IL USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Ai
authors.affiliation: Rush University; Cohn Research Building; Chicago, IL USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
keywords: AP-1, activator protein-1; AvrA; CD, crohn's disease; CFU, colony-forming unit; DMEM, Dulbecco's modified eagle's medium; FBS, fetal bovine serum; HBSS, Hank's balanced salt solutions; IBD, inflammatory bowel diseases; JNK; JNK, c-jun N-terminal kinase; MAPKKs, mitogen-activated protein kinase kinases; PBS, phosphate buffered saline; Salmonella; TER, transepithelial resistance; TJ, tight junctions; TTSS III, type III secretory system; ZO, zonula occludens; ZO-1; c-Jun; epithelial cell; inflammation; intestine; permeability; tight junction
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