Entamoeba histolytica cysteine proteinase 5 binds integrin on colonic cells and stimulates NFkappaB-mediated pro-inflammatory responses.
Integrins are important mammalian receptors involved in normal cellular functions and the pathogenesis of inflammation and disease. Entamoeba histolytica is a protozoan parasite that colonizes the gut, and in 10% of infected individuals, causes amebic colitis and liver abscess resulting in 10(5) deaths/year. E. histolytica-induced host inflammatory responses are critical ... in the pathogenesis of the disease, yet the host and parasite factors involved in disease are poorly defined. Here we show that pro-mature cysteine proteinase 5 (PCP5), a major virulent factor that is abundantly secreted and/or present on the surface of ameba, binds via its RGD motif to α(V)β(3) integrin on Caco-2 colonic cells and stimulates NFκB-mediated pro-inflammatory responses. PCP5 RGD binding to α(V)β(3) integrin triggered integrin-linked kinase(ILK)-mediated phosphorylation of Akt-473 that bound and induced the ubiquitination of NF-κB essential modulator (NEMO). As NEMO is required for activation of the IKKα-IKKβ complex and NFκB signaling, these events markedly up-regulated pro-inflammatory mediator expressions in vitro in Caco-2 cells and in vivo in colonic loop studies in wild-type and Muc2(-/-) mice lacking an intact protective mucus barrier. These results have revealed that EhPCP5 RGD motif is a ligand for α(V)β(3) integrin-mediated adhesion on colonic cells and represents a novel mechanism that E. histolytica trophozoites use to trigger an inflammatory response in the pathogenesis of intestinal amebiasis.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Animals, Blotting, Western, Caco-2 Cells, Cysteine Proteases, Cytokines, Dysentery, Amebic, Entamoeba histolytica, Host-Pathogen Interactions, Humans, I-kappa B Kinase, Immunoprecipitation, Inflammation, Integrin alphaVbeta3, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucin-2, NF-kappa B, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-akt, Protozoan Proteins
Amino Acid Motifs, Amino Acid Sequence, Animals, Blotting, Western, Caco-2 Cells, Cysteine Proteases, Cytokines, Dysentery, Amebic, Entamoeba histolytica, Host-Pathogen Interactions, Humans, I-kappa B Kinase, Immunoprecipitation, Inflammation, Integrin alphaVbeta3, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucin-2, NF-kappa B, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-akt, Protozoan Proteins
J. Biol. Chem.
Date: Nov. 12, 2010
PubMed ID: 20837477
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