OTULIN: a master regulator of linear ubiquitin homeostasis in immune signaling, inflammation, and disease

OTU deubiquitinase with linear linkage specificity (OTULIN) is the only deubiquitinase known to exhibit strict specificity for Met1-linked linear ubiquitin chains, serving as a critical regulator that restrains linear ubiquitin chain assembly complex and maintains inflammatory homeostasis and tissue integrity. Advances over recent years have reshaped our understanding of OTULIN from a negative regulator confined to the canonical nuclear factor kappa-light-chain-enhancer of activated B cells pathway to a central editor governing linear ubiquitin network homeostasis. Its functional repertoire spans receptor-proximal inflammatory signaling, cell death fate determination, inflammasome activation, autophagy, and cellular stress adaptation. Emerging evidence from human genetics and animal models has further broadened the OTULIN-associated disease spectrum, revealing that pathogenesis arises from imbalanced linear ubiquitin networks coupled with cell type and tissue context dependent inflammatory dysregulation. Here, we provide a comprehensive overview of OTULIN's structural features, regulatory mechanisms, biological functions, roles in pathogenesis, and potential therapeutic intervention strategies, aiming to inform future mechanistic studies and facilitate translational advances in targeted therapies.