NFKBIB methylation by SETD3 controls NF-κB-mediated interferon activation during viral infection.

The activation and regulation of type I interferon (IFN-I) is essential for the antiviral response and while epigenetic modifiers are known for regulating cellular signaling and responses by modifying nonhistone substrates, their role in IFN-I signaling remains uncertain. Here, through high-throughput screening, we identified the methyltransferase SETD3 as a positive regulator of IFN-I signaling. Specifically, deficiency of SETD3 markedly compromised the innate immune response to various stimuli. Mechanistically, SETD3 mediates NFKBIB methylation on lysine 235 which reinforces the binding of NFKBIB to P62. This promotes the autophagic degradation of NFKBIB and the subsequent release and nuclear translocation of NF-κB, ultimately regulating the transcription of downstream genes. Thus, we reveal the critical role of SETD3-mediated NFKBIB methylation in enhancing IFN-I signaling, highlighting the potential of SETD3 in controlling viral infections.