1. Academic Validation
  2. E3 ubiquitin ligase Nedd4 is a key negative regulator for non-canonical inflammasome activation

E3 ubiquitin ligase Nedd4 is a key negative regulator for non-canonical inflammasome activation

  • Cell Death Differ. 2019 Nov;26(11):2386-2399. doi: 10.1038/s41418-019-0308-7.
Qingjun Liu 1 Shihui Zhang 2 Zhongjie Sun 3 Xiao Guo 3 Hong Zhou 4
Affiliations

Affiliations

  • 1 Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Taiping Road 27, Haidian District, 100850, Beijing, China. [email protected].
  • 2 Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Taiping Road 27, Haidian District, 100850, Beijing, China.
  • 3 Newish technology (Beijing) Co., Economic and Technical Development Zone Ltd., Xihuan South Road 18, 100176, Beijing, China.
  • 4 Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Taiping Road 27, Haidian District, 100850, Beijing, China. [email protected].
Abstract

The non-canonical inflammasome plays important roles in endotoxic shock and Pyroptosis. Murine caspase-11, corresponding to human caspase-4, is centrally located in the non-canonical inflammasome pathway, which is directly activated by cytosolic lipopolysaccharide. It has been reported that ubiquitination strictly regulates inflammatory responses. However, the role of ubiquitination in regulating the non-canonical inflammasome is little known. In this study, we show that the E3 ubiquitin ligase, Nedd4 is an important negative regulatory component of the non-canonical inflammasome pathway. 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.

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