Nucleophosmin Is Cleaved and Inactivated by the Cytotoxic Granule Protease Granzyme M during Natural Killer Cell-mediated Killing

Natural killer (NK) cells kill virus-infected or transformed target cells by delivering cytotoxic proteases called granzymes to the target cell cytosol. One of these proteases, granzyme M, is specifically expressed in NK cells and is thought to instigate a form of cell death distinct from that mediated by granzyme A or granzyme B. However, the mechanism of granzyme M-induced cell death is unclear at present, and few substrates for this granzyme have been reported to date. Here we show that the abundant nucleolar phosphoprotein, nucleophosmin (NPM), is cleaved and inactivated by granzyme M. NPMis essential for cell viability as RNA interference-mediated ablation of NPM expression in human cells resulted in spontaneous apoptosis. Significantly, overexpression of wild-type NPM rescued cells treated with NPM small interference RNA, whereas overexpression of the granzyme M-cleaved form of NPM did not. Because NPMis essential for cell viability, these data suggest that targeting of NPM by granzyme M may contribute to tumor cell eradication by abolishing NPM function.