Deltex E3 ubiquitin ligase 2 potentiates STING-mediated type I interferon response by K63-linked ubiquitination

Stimulator of interferon genes (STING) signaling, as a pivotal DNA-sensing mechanism, orchestrates antiviral and antitumor immunity through the induction of type I interferon response. Precise modulation of STING signaling is critical for maintaining immune homeostasis, yet its regulatory landscape has not been fully elucidated. Here, we identify the Deltex E3 ubiquitin ligase 2 (DTX2) as a positive regulator of STING-type I interferon response. Loss of Dtx2 in mouse macrophages and embryonic fibroblasts (MEFs) markedly impairs the type I interferon production upon double-stranded DNA (dsDNA) or cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) stimulation. Correspondingly, Dtx2^-/- mice exhibit more susceptibility to DNA viral infection compared to its counterparts. Mechanistically, DTX2 interacts with STING to promote K63-linked ubiquitination at residue K236 and K370, which facilitates the translocation of STING from the endoplasmic reticulum (ER) to the Golgi apparatus and activates downstream signaling cascades. Furthermore, we demonstrate that DTX2 potentiates STING-mediated type I interferon response in multiple tumor cell lines, and enhances anti-tumor immunity in murine head and neck cancer models. Collectively, our work uncovers DTX2 as a previously unrecognized regulator of STING, revealing a ubiquitin-dependent mechanism for fine-tuning innate immune response with implications for combating infections and cancer.