Caspase8 is a crucial protease that regulates various signaling pathways, including cell death and inflammation. Mice deficient in Caspase8, with co-deletion of RIPK3 or MLKL, exhibit remarkable resistance to lethal endotoxin shock. However, the underlying mechanisms for this resistance remain elusive. In this study, as CYLD was identified as a substrate for Caspase8 cleavage, we generated CYLD D215A (resistant to Caspase8 cleavage) mutant mice (CyldD215A/D215A) that develop normally. Surprisingly, CyldD215A/D215A mice exhibited significant protection against lethal endotoxin shock. Furthermore, the removal of Cyld in Caspase8-/-Mlkl-/- mice significantly restored sensitivity to endotoxin shock, thus confirming that maintaining CYLD stability is responsible for the resistance observed in Caspase8-/-Mlkl-/- mice. Mechanistically, CYLD specifically regulates M1-linked deubiquitylation on the K301/303 residues of P65, thereby modulating the nuclear translocation of P65 mediated NF-kB activation. Notably, the cleaved N-terminal fragment of CYLD (named CP25) can be secreted through a TRIF/FADD/Caspase8-dependent pathway and detected in serum, suggesting its potential as an inflammatory biomarker. These findings highlight the CYLD cleavage as a potential therapeutic target and diagnostic marker for endotoxin shock.
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