| First Author | Zhu F | Year | 2023 |
| Journal | Immunity | Volume | 56 |
| Issue | 4 | Pages | 753-767.e8 |
| PubMed ID | 37001519 | Mgi Jnum | J:334741 |
| Mgi Id | MGI:7463870 | Doi | 10.1016/j.immuni.2023.03.003 |
| Citation | Zhu F, et al. (2023) The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome. Immunity 56(4):753-767.e8 |
| abstractText | 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. |
