Wang W, Uzzau S, Goldblum S E, Fasano A
Division of Pediatric Gastroenterology and Nutrition, Gastrointestinal Pathophysiology Section, Center for Vaccine Development, Baltimore, MD 21201, USA.
J Cell Sci. 2000 Dec;113 Pt 24:4435-40. doi: 10.1242/jcs.113.24.4435.
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.
细胞间紧密连接是参与水和电解质跨肠上皮细胞向量运输的动态结构。霍乱弧菌产生的小带闭合毒素与特定的肠上皮表面受体相互作用，随后激活一系列复杂的细胞内事件级联反应，从而调节紧密连接的通透性。我们推测这种毒素可能模拟了一种在功能和免疫上与肠紧密连接相关的内源性调节剂的作用。利用亲和纯化的抗小带闭合毒素抗体和尤斯灌流小室测定法，在胎儿和成人的肠道中筛选一种或多种哺乳动物小带闭合毒素类似物。鉴定出一种新型蛋白质——闭合蛋白，它能诱导安装在尤斯灌流小室中的非人灵长类动物肠上皮细胞的紧密连接解体。通过比较活性小带闭合毒素片段和闭合蛋白中的氨基酸，确定了这两种蛋白质N端区域内的假定受体结合域。闭合蛋白可能在发育、生理和病理过程中的紧密连接调节中起关键作用，这些过程包括组织形态发生、肠腔与间质之间液体、大分子和白细胞的移动，以及炎症/自身免疫性疾病。
