E3 ligase UHRF2 hijacks nuclear TBK1 to epigenetically repress type I interferons expression.

The rapid induction of type I interferons (IFN-I) by innate signaling is indispensable for host defense; however, its uncontrolled expression invariably leads to autoimmune diseases. Here, we reveal that the E3 ubiquitin ligase UHRF2 functions as a highly specific epigenetic repressor of IFN-I gene transcription. During viral infection, activated TBK1 undergoes nuclear translocation, where it is hijacked by UHRF2 to achieve gene-specific targeting at IFN-I loci. Upon recruitment to IFN-I loci, UHRF2 physically interacts with histone deacetylase 1 (HDAC1), catalyzes atypical K29-linked polyubiquitination and prevents HDAC1 from degradation. This stabilized UHRF2-HDAC1 complex actively erases the lactylation of histone H4 at lysine 12 (H4K12la), thereby silencing IFN-I transcription. To mount an effective initial antiviral response, IFN-I signaling feedback transiently downregulates UHRF2 expression. Consequently, UHRF2-deficient mice exhibit profound resistance to lethal virus infection in vivo due to IFN-I overproduction. These findings uncover a highly coordinated mechanism wherein nuclear TBK1, UHRF2, and HDAC1 converge to epigenetically regulate immune homeostasis through histone delactylation, identifying UHRF2 as a potential therapeutic target for virus infection or autoimmune diseases.