Abstract
Caspases are key mediators of apoptosis. Using a novel expression cloning strategy we recently developed to identify cDNAs encoding caspase substrates, we isolated the intermediate filament protein vimentin as a caspase substrate. Vimentin is preferentially cleaved by multiple caspases at distinct sites in vitro, including Asp85 by caspases-3 and-7 and Asp259 by caspase-6, to yield multiple proteolytic fragments. Vimentin is rapidly proteolyzed by multiple caspases into similar sized fragments during apoptosis induced by many stimuli. Caspase cleavage of vimentin disrupts its cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Moreover, caspase proteolysis of vimentin at Asp85 generates a pro-apoptotic amino-terminal fragment whose ability to induce apoptosis is dependent on caspases. Taken together, our findings suggest that caspase proteolysis of vimentin promotes apoptosis by dismantling intermediate filaments and by amplifying the cell death signal via a pro-apoptotic cleavage product.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 443-450 |
| Number of pages | 8 |
| Journal | Cell Death and Differentiation |
| Volume | 8 |
| Issue number | 5 |
| DOIs | |
| State | Published - 2001 |
Funding
We are indebted to Dr. R Talanian for providing the recombinant caspases used in this study, to Drs. I Sanchéz and J Yuan for the caspase-8 dominant negative cDNA, and to Drs. Harris Perlman and Z Oltvai for their critical reading of the manuscript. This work was supported in part by Mentored Clinical Scientist Development Award K08-CA01752 (to VL Cryns) and R01 AR41836 (to KJ Green) from the NIH, by institutional research grants to Northwestern University from the Howard Hughes Medical Institute and the American Cancer Society (to VL Cryns), and by the Elizabeth Boughton Trust (to VL Cryns).
Keywords
- Caspases
- Cytoskeleton
- Intermediate filaments
- Proteases
- Vimentin
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology