NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis
Qinglin Li, Fengping Zhang, Hai Wang, Yingmu Tong, Yunong Fu, Kunjin Wu, Jing Li, Cong Wang, Zi Wang, Yifan Jia, Rui Chen, Yang Wu, Ruixia Cui, Yi Wu, Yun Qi, Kai Qu, Chang Liu, Jingyao Zhang
Abstract
Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical pyroptosis and acetaminophen-induced liver injury.