Ubiquitination is a reversible posttranslational modification in which ubiquitin is covalently attached to substrates at catalysis by E1, E2, and E3 enzymes. As the only E3 ligase for assembling linear ubiquitin chains in animals, the LUBAC complex exerts an essential role in the wide variety of cellular activities. Recent advances in the LUBAC complex, including structure, physiology, and correlation with malignant diseases, have enabled the discovery of potent inhibitors to treat immune-related diseases and cancer brought by LUBAC complex dysfunction. In this review, we summarize the current progress on the structures, physiologic functions, inhibitors of LUBAC, and its potential role in immune diseases, tumors, and other diseases, providing the theoretical basis for therapy of related diseases targeting the LUBAC complex.
