Published 16 September 2002. doi:10.1083/jcb1586iti1
© The Rockefeller University Press,
0021-9525/2002/9/991 $5.00
The Journal of Cell Biology, Volume 158, Number 6, September 16, 2002 991-991
DEDD spells death to caspase substrates
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DEDD (red) brings active caspase-3 (green) to its substrates.
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The major apoptotic effector protein caspase-3 holds the power to destroy a huge number of proteins in a cell—over 34 thousand human proteins with a caspase-3 cleavage motif have been sequenced. Nevertheless, apoptosis proceeds in an ordered fashion; only specific substrates are cleaved at the proper time. On page 1051, Lee et al. describe a new function of the apoptosis regulator DEDD as a scaffolding protein that directs this orderly destruction.
DEDD works by bringing together the important participants, much like scaffolding proteins that control signaling cascades. DEDD resides mainly in the cytosol, despite its previous identification based on its DNA-binding death effector domain (DED). Localization studies by Lee et al. revealed that, even in nonapoptotic epithelial cells, DEDD associated with the keratin intermediate filament network. Once apoptosis was induced, an apoptosis-related epitope within the DED of DEDD was exposed in a caspase-3–dependent manner.
Activated DEDD returns the favor by bringing caspase-3 to its keratin substrate. Active caspase-3 localized almost entirely to keratin filaments, suggesting that keratin is its main substrate in epithelial cells. Later in apoptosis, DEDD, caspase-3, and fragments of keratin filaments formed inclusion bodies that eventually moved into apoptotic blebs.
Ubiquitination of DEDD at apoptosis may regulate its scaffolding activity, as keratin and caspase-3 only associated with diubiquitinated DEDD. When DEDD could not be ubiquitinated, keratin filaments remained intact. Caspase-3 also remained largely inactive, indicating that DEDD further activates the protease and thereby regulates the destruction of substrates beyond keratin. The lag between the initial activation of caspase-3 by cytochrome c and later caspase-3 activation by DEDD may ensure that only small amounts of the protease are active until it reaches its main cytoskeletal target. 
Nicole LeBrasseur
lebrasn{at}rockefeller.edu
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