Nuclear U1 snRNA facilitates the dimerization of hnRNPA2B1 to enhance anti-DNA viral innate immunity

Housekeeping U1 small nuclear RNA (snRNA) is mainly located in the nucleus, which is essential for RNA splicing. Here, we show that seven U1 genes and mature U1 snRNA are upregulated in the nucleoplasm during DNA virus HSV-1 infection. Overexpression of U1 promotes antiviral immunity against HSV-1 infection in vitro and in vivo, while knockdown of U1 via oral delivery of siRNA attenuates anti-DNA viral responses in mice. Macrophages from U1 myeloid cell-specific knockin (U1^mKI) mice show stronger antiviral immunity. Adoptive transfer of U1^mKI macrophages or oral delivery of U1 protects mice against HSV-1. Mechanistically, U1 interacts with the nuclear DNA sensor hnRNPA2B1 to facilitate its dimerization, nucleocytoplasmic translocation, and downstream TBK1-IRF3 signaling activation, thereby enhancing the induction of type I interferon during HSV-1 infection. Our study reveals an uncharacterized role of nuclear U1 in boosting host anti-DNA viral innate immunity and provides strategies for restricting DNA virus infection.