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J. Biol. Chem., Vol. 278, Issue 9, 6848-6853, February 28, 2003
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From the Caspase cleavage of key cytoskeletal proteins,
including several intermediate filament proteins, triggers the dramatic
disassembly of the cytoskeleton that characterizes apoptosis. Here we
describe the muscle-specific intermediate filament protein desmin as a novel caspase substrate. Desmin is cleaved selectively at a conserved Asp residue in its L1-L2 linker domain (VEMD
Caspase Proteolysis of Desmin Produces a Dominant-negative
Inhibitor of Intermediate Filaments and Promotes Apoptosis*
,,,¶
Division of Endocrinology, Metabolism, and
Molecular Medicine, Department of Medicine, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois 60611 and the
§ Department of Molecular and Cellular Biology, Baylor
College of Medicine, Houston, Texas 77030
M264)
by caspase-6 in vitro and in myogenic cells undergoing
apoptosis. We demonstrate that caspase cleavage of desmin at
Asp263 has important functional consequences, including the
production of an amino-terminal cleavage product, N-desmin, which is
unable to assemble into intermediate filaments, instead forming large intracellular aggregates. Moreover, N-desmin functions as a
dominant-negative inhibitor of filament assembly, both for desmin and
the structurally related intermediate filament protein vimentin. We
also show that stable expression of a caspase cleavage-resistant desmin
D263E mutant partially protects cells from tumor necrosis
factor-
-induced apoptosis. Taken together, these results
indicate that caspase proteolysis of desmin at Asp263
produces a dominant-negative inhibitor of intermediate filaments and
actively participates in the execution of apoptosis. In addition, these
findings provide further evidence that the intermediate filament
cytoskeleton has been targeted systematically for degradation during apoptosis.
*
This work was supported in part by a grant from the Muscular
Dystrophy Association (to V. L. C.), Grant NS31957 from the National Institutes of Health (to V. L. C.), an institutional research grant
to Northwestern University from the Howard Hughes Medical Institute (to
V. L. C.), and the Elizabeth Boughton Trust (to V. L. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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