Activation of NF-kappaB during viral infection is one of the critical elements in innate immune response. Several virus-specific factors, such as double-stranded RNA, can trigger host defense mechanisms by inducing NF-kappaB-mediated expression of cytokines and interferons. Early stages of poliovirus infection are also associated with degradation of IkappaB alpha and translocation of NF-kappaB into the nucleus. However, at later stages of poliovirus replication the p65-RelA component of the NF-kappaB complex undergoes a specific cleavage that coincides with the onset of intensive poliovirus protein synthesis and the appearance of the activity of poliovirus protease 3C. Indeed, the p65-RelA amino acid sequence contains the recognition site for 3C, and recombinant protein 3C was shown to be capable of proteolytic cleavage of p65-RelA, generating truncated product similar to that observed during poliovirus infection. Cleavage of p65-RelA occurs during replication of ECHO-1 and rhinovirus 14, suggesting that inactivation of NF-kappaB function by proteolytic cleavage of p65-RelA is the common mechanism by which picornaviruses suppress the innate immune response.