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First published online 30 March 2004
doi: 10.1242/jcs.01071
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Research Article |
1 Institute of Clinical Chemistry and Pathobiochemistry, Charité – Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
2 Institute of Biochemistry, Deutscher Platz 6, 04103 Leipzig, Germany
3 Institute of Biochemistry, Fabeckstrasse 36A, 14195 Berlin, Germany
4 Department of Gastroenterology, Charité – Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
5 Institute of Clinical Physiology, Charité – Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
* Author for correspondence (e-mail: otmar.huber{at}charite.de)
Accepted 30 December 2003
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 Asp320 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.
Key words: Apoptosis, Tight junctions, Occludin, Caspase, Metalloproteinase
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