Protein ubiquitination controls protein degradation and signal transduction, ultimately affecting every cellular process. A variety of functions are mediated by different types of ubiquitin chains, among which, the linear ubiquitin chains, assembled by the ubiquitin ligase LUBAC and removed by the deubiquitinase OTULIN, play fundamental roles in tissue homeostasis and disease development. We previously demonstrated that OTULIN allies with LUBAC to govern angiogenesis by editing ALK1 linear polyubiquitin (Molecular Cell, 2021), and we further established a systematic HOIP interactome profiling revealing critical roles of linear ubiquitination in tissue homeostasis (Nature Communications, 2024). More recently, we uncovered a linear ubiquitination-governed spatiotemporal regulatory mechanism that fine-tunes STING-driven antiviral immunity. Specifically, we found that during DNA viral infection, LUBAC and OTULIN reversibly catalyze the linear ubiquitination of STING. At the early stage of the infection, LUBAC promotes STING linear ubiquitination to drive its trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus through binding to the Sec24b subunit of the coat protein complex II (COPII) complex. Later on, OTULIN is recruited to TANK1 binding kinase 1 (TBK1)-phosphorylated STING and removes its linear ubiquitin chains, thus preventing excessive antiviral immune responses (Advanced Science, 2025). Collectively, our studies have provided mechanistic insights into linear ubiquitination-mediated physiological and pathological processes, which suggests potential drug targets for various linear ubiquitin-associated diseases.