Abstract
Critical to the pathogenesis of intestinal amebiasis, Entamoeba histolytica (Eh) induces mucus hypersecretion and degrades the colonic mucus layer at the site of invasion. The parasite component(s) responsible for hypersecretion are poorly defined, as are regulators of mucin secretion within the host. In this study, we have identified the key virulence factor in live Eh that elicits the fast release of mucin by goblets cells as cysteine protease 5 (EhCP5) whereas, modest mucus secretion occurred with secreted soluble EhCP5 and recombinant CP5. Coupling of EhCP5-αvβ3 integrin on goblet cells facilitated outside-in signaling by activating SRC family kinases (SFK) and focal adhesion kinase that resulted in the activation/phosphorlyation of PI3K at the site of Eh contact and production of PIP3. PKCδ was activated at the EhCP5-αvβ3 integrin contact site that specifically regulated mucin secretion though the trafficking vesicle marker myristoylated alanine-rich C-kinase substrate (MARCKS). This study has identified that EhCP5 coupling with goblet cell αvβ3 receptors can initiate a signal cascade involving PI3K, PKCδ and MARCKS to drive mucin secretion from goblet cells critical in disease pathogenesis.
Highlights
The secreted polymeric mucin layer that lies above the host epithelium forms the first line of innate host defense within the gastrointestinal tract [1]
To determine if cysteine protease activity was involved in mucin secretion, WTEh were pretreated with the cysteine protease inhibitor E64
3H-mucin secretion from WTEh + E64 was significantly less than WTEh and was similar to Eh cysteine proteinase 5 (EhCP5)
Summary
The secreted polymeric mucin layer that lies above the host epithelium forms the first line of innate host defense within the gastrointestinal tract [1]. The principal mucin present in the colonic mucus layer is MUC2, a heavily glycosylated protein composed of a 5179 amino acid backbone and mostly O-linked sugars [3,4,5]. MUC2 is mainly composed of galactose, N-acetylgalactosamine, N-acetylglucosamine with terminal fucose and sialic acid residues that are often targeted by microbes via adherence lectins [7,8]. It is likely these sugar moieties present on MUC2 act as decoys to keep the indigenous microbiota and pathogenic organisms spatially separated from the host epithelium [1]
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