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

Noncytotoxic Inhibition of Cytomegalovirus Replication through NK Cell Protease Granzyme M-Mediated Cleavage of Viral Phosphoprotein 71

“…The major mechanism by which GrM induces host cell death is poorly understood, and some aspects remain controversial. Several studies have reported that GrM induces a perforin-dependent cell death pathway independent of caspase activation and mitochondrial perturbation (21,23,24). In contrast, another study has proposed that GrM causes loss of mitochondrial membrane potential and subsequently triggers caspase-dependent apoptosis (20).…”

“…Previously, we have shown that GrM efficiently cleaves the microtubule network component a-tubulin (23), which plays an essential role in the host cellular machinery for viral intracellular transport (46). In addition, GrM cleaves the nuclear phosphoprotein nucleophosmin in tumor cells (24). Nucleophosmin has been implicated in viral progression, with a number of viral proteins using the shuttling capacity of nucleophosmin to gain access to the host cell nucleus (47,48).…”

“…Although GrA and GrB have been well studied, little is known about the functions of the other human Grs. GrM, which is highly expressed by NK cells (18,19), induces a specialized mode of cell death that affects mitochondrial integrity (20)(21)(22)(23)(24). GrM-deficient mice display increased susceptibility to murine CMV (MCMV) infection, indicating the physiological importance of GrM in CMV clearance in vivo (25).…”

A quarter century of granzymes

“…80 In support of this finding, another group also reported GrM-killing induced cell swelling and permeability to PI, was insensitive to zVAD-fmk, and did not activate caspase-3. 81 In contrast, Zuzen Fan's group reported recombinant GrM delivered by a cationic liposome reagentinduced rapid cell lysis ( 51 Cr-release), phosphatidylserine exposure (but remained largely impermeable to PI), and DNA fragmentation. Cell death readouts were also sensitive to zVAD-fmk, as caspase-3 was activated by an undetermined mechanism.…”

“…Of interest, these results have recently been refuted. 81 Fan's group has also reported the release of cytochrome C, ROS production, Dc m dissipation (through a cyclosporine-A-sensitive mechanism), and GrM-proteolysis of heat shock protein 70, a protein that protects cells from ROS damage. 83 GrM also disrupts the microtubule network of cells in the presence of zVAD-fmk, and specifically targets ezrin and a-tubulin at numerous cleavage sites.…”