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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
Abstract:
Apoptosis depends critically on regulated cytoskeletal reorganizationevents in a cell. We demonstrate that death effector domaincontaining DNA binding protein (DEDD), a highly conserved andubiquitous death effector domain containing protein, existspredominantly as mono- or diubiquitinated, and that diubiquitinatedDEDD interacts with both the K8/18 intermediate filament networkand pro–caspase-3. Early in apoptosis, both cytosolicDEDD and its close homologue DEDD2 formed filaments that colocalizedwith and depended on K8/18 and active caspase-3. Subsequently,these filamentous structures collapsed into intracellular inclusionsthat 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 coimmunoprecipitatedwith both K18 and pro–caspase-3, and kinetic analysesplaced apoptotic DEDD staining prior to caspase-3 activationand K18 cleavage. In addition, both caspase-3 activation andK18 cleavage was inhibited by expression of DEDDNLS1-3, a cytosolicform of DEDD that cannot be ubiquitinated. Finally, siRNA mediatedDEDD knockdown cells exhibited inhibition of staurosporine-inducedDNA degradation. Our data suggest that DEDD represents a novelscaffold protein that directs the effector caspase-3 to certainsubstrates facilitating their ordered degradation during apoptosis.
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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. 
