Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis

Cell Death Differ. 2001 May;8(5):443-50. doi: 10.1038/sj.cdd.4400840.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis* / drug effects
  • Aspartic Acid / metabolism
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspase 6
  • Caspase 7
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Line
  • Cloning, Molecular
  • Cycloheximide / pharmacology
  • Electrophoresis, Polyacrylamide Gel
  • HeLa Cells
  • Humans
  • Intermediate Filaments / drug effects
  • Intermediate Filaments / metabolism*
  • Microfilament Proteins / metabolism
  • Mutation / genetics
  • Protein Processing, Post-Translational / drug effects
  • Staurosporine / pharmacology
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vimentin / chemistry
  • Vimentin / genetics
  • Vimentin / metabolism*

Substances

  • Carrier Proteins
  • Caspase Inhibitors
  • Microfilament Proteins
  • Tumor Necrosis Factor-alpha
  • Vimentin
  • fodrin
  • Aspartic Acid
  • Cycloheximide
  • CASP3 protein, human
  • CASP6 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 6
  • Caspase 7
  • Caspases
  • Staurosporine