Regulatory mechanism of DNMT3A in interferon expression inhibition by Newcastle disease virus V protein

Newcastle disease, caused by the Newcastle disease virus (NDV) and characterised by rapid onset and high mortality rates, is a highly contagious disease in the poultry industry. Interferons (IFN) play a key role in host defence against NDV, however, the non-structural protein V of NDV can antagonise IFN to facilitate NDV immune escape. DNA methyltransferase (DNMT)3A, an important regulator of IFN signalling molecules, may participate in the process by which the V protein inhibits IFN. Here, we found that NDV and V protein can inhibit DNMT3A expression, and DNMT3A participates in V protein inhibition of IFN expression. Further analysis revealed that the V protein interacts with DNMT3A and promotes its degradation via the K48-ubiquitin pathway. DNMT3A enhances the transcription and expression of IFN-β without altering the methylation status of the IFN-β gene. Instead, DNMT3A reduces the methylation of the CpG island in the IRF7 promoter region and increases the overall CpG island methylation within the IRF7 gene body, thereby increasing IRF7 expression and modulating IFN-β expression. Our study shows that NDV V protein can bind to and degrade DNMT3A, thereby affecting the methylation level of IRF7 and inhibiting IRF7 expression, ultimately leading to decreased IFN-β expression.