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<p>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 (<i>Cyld</i><sup><i>D215A/D215A</i></sup>), rendering CYLD resistant to caspase8 cleavage, exhibited marked protection against lethal endotoxic shock. Moreover, deletion of <i>Cyld</i> in <i>Caspase8</i><sup><i>−/−</i></sup><i>Mlkl</i><sup><i>−/−</i></sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月18日

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  • Jianling Liu,
  • Ming Li,
  • Mingyan Xing,
  • Han Liu,
  • Xiaoxia Wu,
  • Lingxia Wang,
  • Xiaoming Li,
  • Xiaoming Zhao,
  • Yangjing Ou,
  • Yue Zhang,
  • Qun Xie,
  • Yongchang Tan,
  • YangYang Wang,
  • YangYang Xie,
  • Hanwen Zhang,
  • Yan Luo,
  • Haibing Zhang

摘要

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 (CyldD215A/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.