FIG. 6.
IFN-related pro- and antiapoptotic pathways down-regulated by NS1. There are two NF-κB-regulated apoptotic pathways. The first one is proapoptotic and IFN dependent. In this pathway viral dsRNA intermediates activate PKR, which initiates phosphorylation and ubiquitination of IκB, an inhibitor of NF-κB. Activated NF-κB, a transcription factor, forms intranuclear enhanceosome complexes containing HMG-1/Y, ATF (also known as c-jun), and PRD-1 as well as IRF 1, 3, and 7 to promote IFN expression. IFN triggers antiviral genes through FNAR-STAT pathways and the IFN-stimulated responsive element. Certain elements in this antiviral program, such as PKR, oligoadenylate synthetase (or RNase L,) are known to initiate apoptosis and induce caspases 1, 3, and 8 (for a review, see reference 19). This is a major cascade in normal IFN-competent cells, such as MDCK and CF cells, and its down-regulation by NS1 delays apoptosis in WT-infected cells. The second pathway is antiapoptotic. It also involves PKR-dependent activation of NF-κB that becomes available for apoptosis inhibitors (IAPs, Bcl-XL, A1/Bfl1, etc.) in IFN-deficient systems, such as Vero cells. Under these conditions, inhibition of PKR by NS1 may promote apoptosis. As a result, apoptosis develops in WT-infected cells more intensively than in delNS1-infected ones. The targets of NS1 interference are indicated.