N-terminal domain of classical swine fever virus Npro induces proteasomal degradation of specificity protein 1 with reduced HDAC1 expression to evade from innate immune responses

Classical swine fever virus (CSFV) poses a major threat to the pig industry. The mechanisms that CSFV uses to evade host innate immunity are not fully understood. Acetylation of histones and non-histone proteins is involved in modulating innate immune responses. Histone deacetylase 1 (HDAC1) could be proviral or antiviral by modulating the acetylation status of histones, viral proteins or non-histone host proteins, depending on the type of viruses involved. First, we found that CSFV infection in IPEC-J2 cells resulted in reduced expression of HDAC1. By chemical inhibition, gene silencing, and overexpression, we revealed that HDAC1 acts as a negative regulator of CSFV replication in IPEC-J2 cells probably through activation of poly(I:C) and IFN-lambda 3-induced IFN-I/III innate immunity. Mechanistically, CSFV N-pro downregulated HDAC1 and its transcriptional regulator specificity protein 1 (Sp1). N-pro interacted with Sp1 to facilitate its degradation through the ubiquitin-proteasome pathway via its N-terminal domain, a region that does not have significant effect on IRF3 stability. Thus, it is clear that CSFV deploys the two domains of its N-pro to counteract the innate immune responses, the C-terminal one targeting the IRF3 pathway as previously reported, and the N-terminal one targeting the Sp1-HDAC1 axis.