Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis.
Caspases are key mediators of apoptosis. Using a novel expression cloning strategy we recently developed to identify cDNAs encoding caspase substrates, we isolated the intermediate filament protein vimentin as a caspase substrate. Vimentin is preferentially cleaved by multiple caspases at distinct sites in vitro, including Asp85 by caspases-3 and -7 and Asp259 by caspase-6, to yield multiple proteolytic fragments. Vimentin is rapidly proteolyzed by multiple caspases into similar sized fragments during apoptosis induced by many stimuli. Caspase cleavage of vimentin disrupts its cytoplasmic network of intermediate filaments and coincides temporally with nuclear fragmentation. Moreover, caspase proteolysis of vimentin at Asp85 generates a pro-apoptotic amino-terminal fragment whose ability to induce apoptosis is dependent on caspases. Taken together, our findings suggest that caspase proteolysis of vimentin promotes apoptosis by dismantling intermediate filaments and by amplifying the cell death signal via a pro-apoptotic cleavage product.
Byun
Y
Y
Center for Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
Chen
F
F
Chang
R
R
Trivedi
M
M
Green
K J
KJ
Cryns
V L
VL
D017209:Apoptosis / Q000187:drug effects; D001224:Aspartic Acid / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D003513:Cycloheximide / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006367:HeLa Cells; D006801:Humans; D007382:Intermediate Filaments / Q000187:drug effects / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014746:Vimentin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013049:Spectrin
D001224:Aspartic Acid; D002352:Carrier Proteins; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D061945:Caspase Inhibitors; D020169:Caspases; D003513:Cycloheximide; D008840:Microfilament Proteins; D019311:Staurosporine; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D013049:Spectrin; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505520:CASP7 protein, human