PEDV nsp1 has been identified as an IFN antagonist, which constrains poly (I:C)-induced IFN-β promoter activity [65]. Nsp1 significantly inhibits the activation of IFN-β promoter triggered by IRF3, whereas it does not inhibit IRF3 phosphorylation and its nuclear translocation. Nsp1 interrupts the association of IRF3 with CREB-binding protein (CBP), by promoting CBP degradation in the nucleus via the proteasome-dependent pathway. CBP/p300, the transcription co-activator cAMP responsive element binding protein (CREB), forms a complex with the activated IRF3 in nucleus. The IRF3-CBP/p300 complex binds to the positive regulatory domain (PRD) regions of the IFN-β promoter, to assemble the enhanceosome with NF-κB and other factors, which ultimately turn on the transcription of type I IFN genes [184,185,186]. Therefore, PEDV nsp1 blocks type I IFN production in the nucleus. Activated NF-κB induces the production of type I IFNs and proinflammatory cytokines and is important for inhibiting viral infection. PEDV nsp1 has been shown to interfere with the NF-κB activity [78] and is the most potent suppressor of proinflammatory cytokines at early infection. It inhibits the phosphorylation and degradation of IκBα, and blocks p65 nuclear translocation, leading to the suppression of both IFN and the early production of pro-inflammatory cytokines [78]. Moreover, PEDV inhibits type III IFN production and nsp1, nsp3, nsp5, nsp8, nsp14, nsp15, nsp16, ORF3, E, M, and N are identified as type III IFN antagonists. Among these antagonists, nsp1 is the most potent suppressor [130]. PEDV nsp1 blocks the nuclear translocation of IRF1 and decreases the amounts of peroxisomes and then suppresses IRF1-mediated type III IFNs. The conserved residues of PEDV nsp1 protein are crucial for IFN suppression [130]. Multiple effects of nsp1 on modulating innate immune response during PEDV infection suggest the vital role of nsp1 in the PEDV replication cycle.