Neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) is an E3 ligase that degrades multiple different proteins and plays an oncogenic role in human cancer. The Nedd4 family E3 ligases are key regulators of cell growth and proliferation and are often misregulated in human cancers and other diseases. The ligase activities of Nedd4 E3s are tightly controlled via auto-inhibition. Nedd4 deficiency promoted mouse death from sepsis and cell pyroptosis, resulting from non-canonical inflammasome activation. Furthermore, Nedd4 induced the K48-linked polyubiquitination and subsequent degradation of caspase-11 through the 26S proteasome. Meanwhile, caspase-11 (or caspase-4) reciprocally regulated the level of Nedd4 protein by cleavage. Thus, Nedd4 appears to have a key role in balancing the level of non-canonical inflammasome activation in response to gram-negative bacterial infection.