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© The Rockefeller University Press, 0021-9525/1997//1379 $5.00
The Journal of Cell Biology, Volume 138, Number 6, , 1997 1379-1394

Article

Caspase Cleavage of Keratin 18 and Reorganization of Intermediate Filaments during Epithelial Cell Apoptosis



Carlos Caulín, Guy S. Salvesen, and Robert G. Oshima

The Burnham Institute (formerly the La Jolla Cancer Research Foundation), La Jolla, California 92037

Keratins 8 (K8) and 18 (K18) are major components of intermediate filaments (IFs) of simple epithelial cells and tumors derived from such cells. Structural cell changes during apoptosis are mediated by proteases of the caspase family. During apoptosis, K18 IFs reorganize into granular structures enriched for K18 phosphorylated on serine 53. K18, but not K8, generates a proteolytic fragment during drug- and UV light–induced apoptosis; this fragment comigrates with K18 cleaved in vitro by caspase-6, -3, and -7. K18 is cleaved by caspase-6 into NH2-terminal, 26-kD and COOH-terminal, 22-kD fragments; caspase-3 and -7 additionally cleave the 22-kD fragment into a 19-kD fragment. The cleavage site common for the three caspases was the sequence VEVD/A, located in the conserved L1-2 linker region of K18. The additional site for caspases-3 and -7 that is not cleaved efficiently by caspase-6 is located in the COOH-terminal tail domain of K18. Expression of K18 with alanine instead of serine at position 53 demonstrated that cleavage during apoptosis does not require phosphorylation of serine 53. However, K18 with a glutamate instead of aspartate at position 238 was resistant to proteolysis during apoptosis. Furthermore, this cleavage site mutant appears to cause keratin filament reorganization in stably transfected clones. The identification of the L1-2 caspase cleavage site, and the conservation of the same or very similar sites in multiple other intermediate filament proteins, suggests that the processing of IFs during apoptosis may be initiated by a similar caspase cleavage.

Abbreviations used in this paper: DAPI, 4, 6-diamidino-2-phenylindole; IF, intermediate filament; K8 and K18, keratins 8 and 18.

Address all correspondence to Robert G. Oshima, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037. Tel.: (619) 646-3147. Fax: (619) 646-3193. e-mail: rgoshima{at}ljcrf.edu


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