DEDD regulates degradation of intermediate filaments during apoptosis

Justine C. Lee, Olaf Schickling, Alexander H. Stegh, Robert G. Oshima, David Dinsdale, Gerald M. Cohen, Marcus E. Peter*

*Corresponding author for this work

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

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 DEDDΔNLS1-3, 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.

Original languageEnglish (US)
Pages (from-to)1051-1066
Number of pages16
JournalJournal of Cell Biology
Volume158
Issue number6
DOIs
StatePublished - Sep 16 2002

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Keywords

  • Apoptosis
  • Caspases
  • DEDD
  • Intermediate filaments
  • Mono-ubiquitination

ASJC Scopus subject areas

  • Cell Biology

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