Caspase-8-mediated CYLD cleavage boosts LPS-induced endotoxic shock

Caspase-8, a key protease in cell death and inflammation, plays a significant role in cytokine production during septic shock, although its precise mechanisms remain unclear. In this study, we found that mice with a specific CYLD mutation at D215 (Cyld^D215A/D215A), rendering CYLD resistant to caspase8 cleavage, exhibited marked protection against lethal endotoxic shock. Moreover, deletion of Cyld in Caspase8^-/-Mlkl^-/- mice restored their sensitivity to endotoxic shock, indicating Caspase8 promotes endotoxic shock by cleaving and degrading CYLD, thereby removing its anti-inflammatory function. Mechanistically, CYLD removes of LUBAC-mediated M1-linked ubiquitination of p65 at K301/K303, thereby suppressing its nuclear translocation and activation, and consequently inhibiting NF-κB-driven inflammatory responses. The CYLD D215A mutation exerts anti-inflammatory effects by resisting Caspase-8-mediated cleavage and degradation. Overall, these findings highlight CYLD cleavage as a promising therapeutic target for combating inflammation in endotoxic shock.