Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis

Caspases are key mediators of apoptosis, Using a novel expression cloning s trategy we recently developed to identify cDNAs encoding caspase substrates , we isolated the intermediate filament protein vimentin as a caspase subst rate, vimentin is preferentially cleaved by multiple caspases at distinct s ites in vitro, including Asp(85) by caspases-3 and -7 and Asp(259) by caspa se-6, to yield multiple proteolytic fragments. Vimentin is rapidly proteoly zed by multiple caspases into similar sized fragments during apoptosis indu ced by many stimuli. Caspase cleavage of vimentin disrupts its cytoplasmic network of intermediate filaments and coincides temporally with nuclear fra gmentation. Moreover, caspase proteolysis of vimentin at Asp(85) generates a pro apoptotic amino-terminal fragment whose ability to induce apoptosis i s dependent on caspases, Taken together, our findings suggest that caspase proteolysis of vimentin promotes apoptosis by dismantling intermediate fila ments and by amplifying the cell death signal via a pro-apoptotic cleavage product.