Human zonulin, a potential modulator of intestinal tight junctions

TLDR

Intestinal tight junctions are dynamic structures that regulate water and electrolyte transport, and the Vibrio cholerae–derived zonula occludens toxin binds a specific epithelial receptor to trigger intracellular signaling that alters junction permeability. The study hypothesizes that a mammalian endogenous protein may mimic the zonula occludens toxin’s effect on intestinal tight junctions. Using affinity‑purified anti‑zonula occludens toxin antibodies and Ussing chamber assays, the authors screened fetal and adult human intestinal tissues for zonula occludens toxin–like proteins. They discovered a novel protein, zonulin, that causes tight junction disassembly in primate intestinal epithelium, mapped its receptor‑binding domain to the N‑terminal region shared with the toxin, and concluded that zonulin plays a central role in regulating tight junctions during development, physiology, and disease.

Abstract

ABSTRACT Intercellular tight junctions are dynamic structures involved in vectorial transport of water and electrolytes across the intestinal epithelium. Zonula occludens toxin derived from Vibrio cholerae interacts with a specific intestinal epithelial surface receptor, with subsequent activation of a complex intracellular cascade of events that regulate tight junction permeability. We postulated that this toxin may mimic the effect of a functionally and immunologically related endogenous modulator of intestinal tight junctions. Affinity-purified anti-zonula occludens toxin antibodies and the Ussing chamber assay were used to screen for one or more mammalian zonula occludens toxin analogues in both fetal and adult human intestine. A novel protein, zonulin, was identified that induces tight junction disassembly in non-human primate intestinal epithelia mounted in Ussing chambers. Comparison of amino acids in the active zonula occludens toxin fragment and zonulin permitted the identification of the putative receptor binding domain within the N-terminal region of the two proteins. Zonulin likely plays a pivotal role in tight junction regulation during developmental, physiological, and pathological processes, including tissue morphogenesis, movement of fluid, macromolecules and leukocytes between the intestinal lumen and the interstitium, and inflammatory/autoimmune disorders.