The viral nucleocapsid protein of transmissible gastroenteritis coronavirus (TGEV) is cleaved by caspase-6 and-7 during TGEV-induced apoptosis

The transmissible gastroenteritis coronavirus (TGEV), like many other virus es, exerts much of its cytopathic effect through the induction of apoptosis of its host cell. Apoptosis is coordinated by a family of cysteine proteas es, called caspases, that are activated during apoptosis and participate in dismantling the cell by cleaving key structural and regulatory proteins. W e have explored the caspase activation events that are initiated upon infec tion of the human rectal tumor cell line HRT18 with TGEV, We show that TGEV infection results in the activation of caspase-3, -6, -7, -8, and -9 and c leavage of the caspase substrates eIF4GI, gelsolin, and alpha-fodrin. Surpr isingly, the TGEV nucleoprotein (N) underwent proteolysis in parallel with the activation of caspases within the host cell. Cleavage of the N protein was inhibited by cell-permeative caspase inhibitors, suggesting that this v iral structural protein is a target for host cell caspases. We show that th e TGEV nucleoprotein is a substrate for both caspase-6 and -7, and using si te-directed mutagenesis, we have mapped the cleavage site to VVPD359 down a rrow. These data demonstrate that viral proteins can be targeted for destru ction by the host cell death machinery.