In this study, we investigated the interplay between CYLD and the TRAF6/sNASP axis, and uncovered a novel functional mechanism of CYLD: that CYLD undergoes separation from the sNASP/TRAF6 complex in sepsis-induced lung innate immunity, which is essential for subsequent TRAF6 autoubiquitination and NF-κB activation. Here, TRAF6 is linked to Sepsis.