Images of hematoxylin and eosin (H&E) staining of the heart and liver of WT and Nedd4 +/− mice showing myocarditis in the heart and large flaky bleeding areas and necrosis in the liver. Error bars indicate the standard deviation (SD) of samples. IL-1β, TNF-ɑ and IL-6 levels in WT and Nedd4 +/− mouse sera were measured at 8 h after re-challenge with LPS. coli O111:B4 LPS, and then challenged with 10 mg/kg E. a Survival of mice primed with 400 μg/kg E. Thus, Nedd4 appears to have a key role in balancing the level of non-canonical inflammasome activation in response to gram-negative bacterial infection.Ĭritical role of Nedd4 in endotoxic shock induced by non-canonical inflammasome activation. Meanwhile, caspase-11 (or caspase-4) reciprocally regulated the level of Nedd4 protein by cleavage. Furthermore, Nedd4 induced the K48-linked polyubiquitination and subsequent degradation of caspase-11 through the 26S proteasome. Nedd4 deficiency promoted mouse death from sepsis and cell pyroptosis, resulting from non-canonical inflammasome activation. In this study, we show that the E3 ubiquitin ligase, Nedd4 is an important negative regulatory component of the non-canonical inflammasome pathway. However, the role of ubiquitination in regulating the non-canonical inflammasome is little known. It has been reported that ubiquitination strictly regulates inflammatory responses. Murine caspase-11, corresponding to human caspase-4, is centrally located in the non-canonical inflammasome pathway, which is directly activated by cytosolic lipopolysaccharide. The non-canonical inflammasome plays important roles in endotoxic shock and pyroptosis.