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

Cell Death and Differentiation
Qingjun LiuHong Zhou

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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Citations

Jun 10, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Sampsa MatikainenWojciech Cypryk
Sep 20, 2021·Journal of Molecular Biology·Skylar S WrightVijay A Rathinam

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Methods Mentioned

BETA
ubiquitination
co-immunoprecipitation
immunoprecipitation
electrophoresis
enzyme-linked immunosorbent assay
ELISA
transfection
X-ray
light microscopy
acetylation

Software Mentioned

SPSS
Sequest
Image
Proteome Discoverer
Pro Plus
Ubipredit
Image Pro Plus

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