The specific fates of tight junction proteins in apoptotic epithelial cells
The specific fates of tight junction proteins in apoptotic epithelial cells
复制标题
DOI：
10.1242/jcs.01071
复制
发表时间：
2004-04-15
影响因子：
4
通讯作者：
Huber, O
中科院分区：
文献类型：
--
作者：
Bojarski, C;Weiske, J;Huber, O
上皮细胞的极化形态取决于特征性细胞间连接的建立和维持。在凋亡上皮细胞中观察到的戏剧性的形态学变化至少部分归因于粘附连接和桥粒组分的特异性片段化。然而，人们对细胞凋亡过程中的紧密连接知之甚少。我们已经发现，在上皮细胞中诱导凋亡后，紧密连接蛋白以与紧密连接破坏相关的独特方式进行蛋白水解裂解。跨膜蛋白occludin以及同样的胞质衔接蛋白ZO-1和ZO-2通过半胱天冬酶切割而片段化。此外，闭合蛋白在细胞外位点被金属蛋白酶切割。occludin中的半胱天冬酶切割位点在C-末端定位于C-末端胞质结构域内的Asp（320）。该位点的突变有效地阻断了片段化。在半胱天冬酶和/或金属蛋白酶抑制剂的存在下，封闭蛋白，ZO-1和ZO-2的片段被阻断，细胞形态几乎完全保留。有趣的是，跨膜紧密连接蛋白的claudin家族的两个成员表现出不同的行为。虽然claudin-2蛋白的量与occludin、ZO-1和ZO-2类似地减少，但claudin-1在凋亡细胞中完全保留或甚至增加。
The polarized morphology of epithelial cells depends on the establishment and maintenance of characteristic intercellular junctions. The dramatic morphological changes observed in apoptotic epithelial cells were ascribed at least in part to the specific fragmentation of components of adherens junctions and desmosomes. Little, however, is known about tight junctions during apoptosis. We have found that after induction of apoptosis in epithelial cells, tight junction proteins undergo proteolytic cleavage in a distinctive manner correlated with a disruption of tight junctions. The transmembrane protein occludin and, likewise, the cytoplasmic adaptor proteins ZO-1 and ZO-2 are fragmented by caspase cleavage. In addition, occludin is cleaved at an extracellular site by a metalloproteinase. The caspase cleavage site in occludin was mapped C-terminally to Asp(320) within the C-terminal cytoplasmic domain. Mutagenesis of this site efficiently blocked fragmentation. In the presence of caspase and/or metalloproteinase inhibitors, fragmentation of occludin, ZO-1 and ZO-2 was blocked and cellular morphology was almost fully preserved. Interestingly, two members of the claudin family of transmembrane tight junction proteins exhibited a different behavior. While the amount of claudin-2 protein was reduced similarly to occludin, ZO-1 and ZO-2, claudin-1 was either fully preserved or was even increased in apoptotic cells.