Nucleophosmin as a direct inhibitor of caspase-6 and -8

Abstract

In acute myelogenous leukemia (AML) with a normal karyotype, a C-terminal frame-shift mutation results in cytoplasmic dislocation of NPM, which may function in cancer pathogenesis1. Here, we demonstrate a role for cytoplasmic NPM in the inhibition of apoptotic signalling. In response to diverse stress agents, nucleoli-bound NPM localises to the cytoplasm with no de novo protein synthesis. NPM specifically inhibits the activities of caspase-6 and a??8 within the cascade, through direct interaction with these caspases using its C-terminal region. It increases the binding of active caspase-6 and a??8 to their substrates, thereby sequestering the active caspases from other available substrates. Cytoplasmic abundance of the NPMc mutant results in excessive inhibition of caspase-8-mediated death receptor signalling, and this is thought to underlie pathogenesis of AML. Our data suggest that cytoplasmic localizated NPM has a cytoprotective role in the regulation of the caspase signalling cascade during stress.