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Published 16 September 2002. doi:10.1083/jcb.200112124
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© The Rockefeller University Press, 0021-9525/2002/9/1051 $5.00
The Journal of Cell Biology, Volume 158, Number 6, September 16, 2002 1051-1066

Article

 DEDD regulates degradation of intermediate filaments during apoptosis

Justine C. Lee1, Olaf Schickling1, Alexander H. Stegh1, Robert G. Oshima2, David Dinsdale3, Gerald M. Cohen3 and Marcus E. Peter1

1 The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637
2 The Burnham Institute, La Jolla, CA 92037
3 Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom

Address correspondence to Marcus Peter, The Ben May Institute for Cancer Research, University of Chicago, 924 E. 57th Street, Chicago, IL 60637. Tel.: (773) 702-4728. Fax: (773) 702-3701. E-mail: MPeter{at}ben-may.bsd.uchicago.edu

Apoptosis depends critically on regulated cytoskeletal reorganization events in a cell. We demonstrate that death effector domain containing DNA binding protein (DEDD), a highly conserved and ubiquitous death effector domain containing protein, exists predominantly as mono- or diubiquitinated, and that diubiquitinated DEDD interacts with both the K8/18 intermediate filament network and pro–caspase-3. Early in apoptosis, both cytosolic DEDD and its close homologue DEDD2 formed filaments that colocalized with and depended on K8/18 and active caspase-3. Subsequently, these filamentous structures collapsed into intracellular inclusions that migrated into cytoplasmic blebs and contained DEDD, DEDD2, active caspase-3, and caspase-3–cleaved K18 late in apoptosis. Biochemical studies further confirmed that DEDD coimmunoprecipitated with both K18 and pro–caspase-3, and kinetic analyses placed apoptotic DEDD staining prior to caspase-3 activation and K18 cleavage. In addition, both caspase-3 activation and K18 cleavage was inhibited by expression of DEDD{Delta}NLS1-3, a cytosolic form of DEDD that cannot be ubiquitinated. Finally, siRNA mediated DEDD knockdown cells exhibited inhibition of staurosporine-induced DNA degradation. Our data suggest that DEDD represents a novel scaffold protein that directs the effector caspase-3 to certain substrates facilitating their ordered degradation during apoptosis.

Key Words: apoptosis; caspases; DEDD; intermediate filaments; monoubiquitination


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