Viral protease cleavage of inhibitor of κBα triggers host cell apoptosis

Apoptosis is an innate immune response to viral infection that limits viral replication. However, the mechanisms by which cells detect viral infection and activate apoptosis are not completely understood. We now show that during Coxsackievirus infection, the viral protease 3C(pro) cleaves inhibitor of kappa B alpha (I kappa B alpha). A proteolytic fragment of I kappa B alpha then forms a stable complex with NF-kappa B, translocates to the nucleus, and inhibits NF-kappa B transactivation, increasing apoptosis and decreasing viral replication. In contrast, cells with reduced I kappa B alpha expression are more susceptible to viral infection, with less apoptosis and more viral replication. I kappa B alpha thus acts as a sensor of viral infection. Cleavage of host proteins by pathogen proteases is a novel mechanism by which the host recognizes and responds to viral infection.