The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology.

A point mutation in OTULIN (OTULINY56A) that disrupts its binding to LUBAC leaves mice viable and free of spontaneous pathology, but highly sensitive to TNF-induced toxicity and to TNF-mediated immunopathology during Listeria monocytogenes infection. The interaction normally limits LUBAC autoubiquitination and Met1-Ub conjugation on non-LUBAC substrates; losing it stabilizes the TNF receptor signaling complex, increases NF-κB signaling, yet protects from TNF-induced apoptosis. The work separates OTULIN-LUBAC binding from OTULIN catalytic function in restraining inflammatory signaling.