The deubiquitinase OTUD4 suppresses TAK1 kinase–dependent NF-κB signaling and inflammation

Chronic inflammation contributes to the development of many cancers, including non-small cell lung cancer, and is characterized by persistent activation of proinflammatory NF-κB signaling. The mechanisms that restrain NF-κB signaling remain incompletely defined. Here, we identify the deubiquitinase ovarian tumor family deubiquitinase 4 (OTUD4) as a suppressor of tumor necrosis factor (TNF)-induced NF-κB activation and chronic inflammation. OTUD4 interacts with core components of the transforming growth factor β-activated kinase 1 (TAK1) signalosome, including TAK1, TAB1, and TAB3, and removes K63-linked polyubiquitin chains from substrates within this complex, such as TAK1 and TAB3, thereby reducing TNF-induced NF-κB signaling. A histidine-centered loop (His loop) in the catalytic domain is required for this K63 linkage specificity. The tumor-associated OTUD4 H148Y missense variant (c.442C>T, p.H148Y), located within this loop, retains TAK1 binding but abolishes intrinsic deubiquitinase activity toward both K63- and K48-linked chains and is associated with sustained NF-κB activation and increased proinflammatory cytokine expression. Collectively, these results reveal a mechanism that suppresses TNF-induced NF-κB signaling and links OTUD4 dysfunction to inflammation-driven oncogenesis, including non-small cell lung cancer.