The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome.

Intracellular sensing of lipopolysaccharide (LPS) by murine caspase-11 or human caspase-4 initiates a protease cascade, termed the non-canonical inflammasome, that results in gasdermin D (GSDMD) processing and subsequent NLRP3 inflammasome activation. In an effort aimed at identifying additional sensors for intracellular LPS by biochemical screening, we identified the nuclear orphan receptor Nur77 as an LPS-binding protein in macrophage lysates. Nr4a1-/- macrophages exhibited impaired activation of the NLRP3 inflammasome, but not caspase-11, in response to LPS. Biochemical mapping revealed that Nur77 bound LPS directly through a domain in its C terminus. Yeast two-hybrid assays identified NLRP3 as a binding partner for Nur77. The association between Nur77 and NLRP3 required the presence of LPS and dsDNA. The source of dsDNA was the mitochondria, requiring the formation of gasdermin-D pores. In vivo, Nur77 deficiency ameliorated host response to endotoxins. Thus, Nur77 functions as an intracellular LPS sensor, binding mitochondrial DNA and LPS to activate the non-canonical NLRP3 inflammasome. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Fangrui Zhu, Juan Ma, Weitao Li, Qiannv Liu, Xiwen Qin, Yan Qian, Chunlei Wang, Yan Zhang, Yi Li, Dong Jiang, Shuo Wang, Pengyan Xia. The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome. Immunity. 2023 Apr 11;56(4):753-767.e8

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PMID: 37001519

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