Pestivirus Npro Directly Interacts with Interferon Regulatory Factor 3 Monomer and Dimer.

The pestivirus N-terminal protease, N(pro), is essential for evading the host's immune system by facilitating the degradation of interferon regulatory factor 3 (IRF3). However, the nature of the N(pro) interaction with IRF3, including the IRF3 species (inactive monomer versus activated dimer) that N(pro) targets for degradation, is largely unknown. We show that classical swine fever virus N(pro) and porcine IRF3 directly interact in solution and that full-length IRF3 is required for interaction with N(pro) Additionally, N(pro) interacts with a constitutively active form of IRF3 bound to its transcriptional cofactor, the CREB-binding protein. This is the first study to demonstrate that N(pro) is able to bind both inactive IRF3 monomer and activated IRF3 dimer and thus likely targets both IRF3 species for ubiquitination and proteasomal degradation.