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Molecular and Cellular Biology, August 2000, p. 5665-5679, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification of the Cytolinker Plectin as a Major Early In Vivo Substrate for Caspase 8 during CD95- and Tumor Necrosis Factor Receptor-Mediated Apoptosis

Alexander H. Stegh,1,2 Harald Herrmann,3 Stefan Lampel,4 Dieter Weisenberger,4 Kerstin Andrä,5 Martin Seper,5 Gerhard Wiche,5 Peter H. Krammer,1 and Marcus E. Peter1,2,*

Tumor Immunology Program,1 Division of Cell Biology,3 and Division Organization of Complex Genomes,4 German Cancer Research Center, D-69120 Heidelberg, Germany; Institute of Biochemistry and Molecular Cell Biology, Vienna Biocenter, University of Vienna, A-1030, Vienna, Austria5; and The Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 606372

Received 29 November 1999/Returned for modification 11 January 2000/Accepted 12 April 2000

Caspase 8 plays an essential role in the execution of death receptor-mediated apoptosis. To determine the localization of endogenous caspase 8, we used a panel of subunit-specific anti-caspase 8 monoclonal antibodies in confocal immunofluorescence microscopy. In the human breast carcinoma cell line MCF7, caspase 8 predominantly colocalized with and bound to mitochondria. After induction of apoptosis through CD95 or tumor necrosis factor receptor I, active caspase 8 translocated to plectin, a major cross-linking protein of the three main cytoplasmic filament systems, whereas the caspase 8 prodomain remained bound to mitochondria. Plectin was quantitatively cleaved by caspase 8 at Asp 2395 in the center of the molecule in all cells tested. Cleavage of plectin clearly preceded that of other caspase substrates such as poly(ADP-ribose) polymerase, gelsolin, cytokeratins, or lamin B. In primary fibroblasts from plectin-deficient mice, apoptosis-induced reorganization of the actin cytoskeleton, as seen in wild-type cells, was severely impaired, suggesting that during apoptosis, plectin is required for the reorganization of the microfilament system.

* Corresponding author. Mailing address: The Ben May Institute for Cancer Research, University of Chicago, 924 E. 57th St., Chicago, IL 60637. Phone: (773) 702-4728. Fax: (773) 702-3701. E-mail: MPeter{at}ben-may.bsd.uchicago.edu.

Molecular and Cellular Biology, August 2000, p. 5665-5679, Vol. 20, No. 15
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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