Disruption of occludin function in polarized epithelial cells activates the extrinsic pathway of apoptosis leading to cell extrusion without loss of transepithelial resistance.
Disruption of occludin function in polarized epithelial cells activates the extrinsic pathway of apoptosis leading to cell extrusion without loss of transepithelial resistance.
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DOI：
10.1186/1471-2121-10-85
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发表时间：
2009-12-09
期刊：
影响因子：
--
通讯作者：
Neville MC
中科院分区：
文献类型：
--
作者：
Beeman NE;Baumgartner HK;Webb PG;Schaack JB;Neville MC
Occludin 是一种四跨膜蛋白，通常位于紧密连接处。该蛋白质与包括病毒和细菌在内的多种病原体相互作用，这种相互作用有时会导致其结外定位。在这里，我们报告用包含在occludin第二个细胞外环LHYH中发现的四个氨基酸序列的环化肽处理乳腺上皮单层，导致结外occludin的出现和外源性细胞凋亡途径的激活。在肽处理后的早期，内源性 occludin 和 LYHY 肽共定位于结外斑块中，这些斑块还显示出含有死亡诱导信号复合物 (DISC)、半胱天冬酶 8 和 3、死亡受体 FAS 和接头分子 FADD 的成分。处理后，occludin 可以与 FADD 进行免疫沉淀，证实其与 DISC 的相互作用。 LYHY 处理后完成挤出，上皮抵抗力没有损失。这些观察结果提供了强有力的证据，表明在破坏后，occludin 与外在死亡受体形成复合物，导致凋亡细胞从上皮单层中挤出。他们认为occludin 在上皮细胞中具有保护作用和屏障形成作用。利用这种蛋白质作为细胞入口点的病原体可能会引发细胞凋亡反应，从而在病原体进入细胞间隙之前将受感染的细胞挤出。
Occludin is a tetraspanin protein normally localized to tight junctions. The protein interacts with a variety of pathogens including viruses and bacteria, an interaction that sometimes leads to its extrajunctional localization. Here we report that treatment of mammary epithelial monolayers with a circularized peptide containing a four amino acid sequence found in the second extracellular loop of occludin, LHYH, leads to the appearance of extrajunctional occludin and activation of the extrinsic apoptotic pathway. At early times after peptide treatment endogenous occludin and the LYHY peptide were co-localized in extrajunctional patches, which were also shown to contain components of the death inducing signaling complex (DISC), caspases 8 and 3, the death receptor FAS and the adaptor molecule FADD. After this treatment occludin could be immunoprecipitated with FADD, confirming its interaction with the DISC. Extrusion after LYHY treatment was accomplished with no loss of epithelial resistance. These observations provide strong evidence that, following disruption, occludin forms a complex with the extrinsic death receptor leading to extrusion of apoptotic cells from the epithelial monolayer. They suggest that occludin has a protective as well as a barrier forming role in epithelia; pathogenic agents which utilize this protein as an entry point into the cell might set off an apoptotic reaction allowing extrusion of the infected cell before the pathogen can gain entry to the interstitial space.
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3.1
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