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, Harald Herrmann, Stefan Lampel, Dieter Weisenberger, Kerstin Andrä, Martin Seper, Gerhard Wiche, Peter H. Krammer, Marcus E. Peter*

*Corresponding author for this work

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5665-5679
Number of pages15
JournalMolecular and Cellular Biology
Volume20
Issue number15
DOIs
StatePublished - Aug 1 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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