Poliovirus protein 3A inhibits tumor necrosis factor (TNF)-induced apoptosis by eliminating the TNF receptor from cell surface

Viral infections often trigger host defensive reactions by activating intri nsic (intracellular) and extrinsic (receptor-mediated) apoptotic pathways. Poliovirus is known to encode an antiapoptotic function(s) suppressing the intrinsic pathway. Here, the effect of poliovirus nonstructural proteins on cell sensitivity to tumor necrosis factor (TN-F)-induced (i.e., receptor-m ediated) apoptosis was studied. This sensitivity is dramatically enhanced b y the viral proteinase 2A, due, most likely, to inhibition of cellular tran slation. On the other hand, cells expressing poliovirus noncapsid proteins 3A and 2B exhibit strong TNF resistance. Expression of 3A neutralizes the p roapoptotic activity of 2A and results in a specific suppression of TNF sig naling, including the lack of activation of NF-kappaB, due to elimination o f the TNF receptor from the cell surface. In agreement with this, polioviru s infection results in a dramatic decrease in TNF receptor abundance on the surfaces of infected cells as early as 4 h postinfection. Poliovirus prote ins that confer resistance to TNF interfere with endoplasmic reticulum-Golg i protein trafficking, and their effect on TNF signaling can be imitated by brefeldin A, suggesting that the mechanism of poliovirus-mediated resistan ce to TNF is a result of aberrant TNF receptor trafficking.