E3 ubiquitin ligase DTX2 reinforces innate antiviral immune responses by modulating K63-linked ubiquitination of TBK1

TBK1 plays a pivotal role in innate antiviral immunity, serving as a critical mediator downstream of various pattern recognition receptors (PRRs). TBK1 activity is tightly regulated by post-translational modifications (PTMs) including ubiquitination to maintain innate immune homeostasis. Here, we identify the Deltex E3 ubiquitin ligase 2 (DTX2) as a positive regulator of innate antiviral signaling in response to RNA viruses. We find that DTX2 overexpression enhances antiviral signaling, whereas loss of DTX2 evidently reduces antiviral responses. Mechanistically, we demonstrated that DTX2 directly interacts with TBK1 and promotes TBK1 K63-linked polyubiquitination to regulate antiviral signaling. Collectively, our study reveals that DTX2 plays a novel positive regulatory role in antiviral signaling by modulating the K63-linked ubiquitination of TBK1 to maintain the balance of innate antiviral immune responses. RNA-seq profiling of wildetype and Dtx2 knockout MEF cells 8 hours after Sendai virus infection.