BEV 2C protein inhibits the NF-κB signalling pathway to promote viral replication by targeting IKBKB and p65

Bovine enterovirus, a member of the Enterovirus genus in the Picornaviridae family, causes severe digestive and respiratory illnesses in cattle. These illnesses threaten the healthy development of the cattle industry. Innate immunity plays a critical role in resisting viral infections, but viruses also use various strategies to evade or counteract the host's immune system. The mechanisms by which bovine enteroviruses evade the host immune response and promote their replication remain unclear. This study used the HY12 strain of enterovirus as a model to investigate its interaction with both bovine enterovirus and its host. Our findings indicate that bovine enterovirus promotes the replication of HY12 by disrupting the NF-κB pathway. Here, one strategy was to down-regulate the IΚBΚB expression to inhibit the activation of NF-κB. Another approach was to directly interact with p65 to reduce the dimerisation of p65/p50 and inhibit the phosphorylation and nuclear translocation of p65. Our study's results show that 2C's N-terminal 1-121 aa is essential for 2C-mediated inhibition of the NF-κB signalling pathway, and four amino acids (position 118-121 aa) are the interaction site of 2C with p65. This report is the first on BEV 2C protein promoting virus replication through new strategies, which provides novel insights into the understanding of enterovirus pathobiology and the development of drugs against BEV.