Mitochondrial SLC25 proteins interact with NLRP3 to regulate inflammasome function
| Autor: | Andrey A. Shuvarikov, Michael A. Davis, Katharina Esser-Nobis, Michael J. Gale |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 200:115.8-115.8 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.200.supp.115.8 |
| Popis: | The NLRP3 protein is a key initiator of inflammation in humans. NLRP3 becomes activated by a multitude of danger signals, including pathogens, markers of metabolic dysfunction, and internalized particulates. Upon activation, NLRP3 nucleates formation of a multiprotein complex called the inflammasome, in which caspase-1 activity mediates processing of the pro-inflammatory cytokines IL-1β and IL-18 and induces pyroptosis, a pro-inflammatory form of cell death that serves to release the mature cytokines along with other inflammatory mediators, thus initiating the inflammatory response. While multiple regulators of the NLRP3 inflammasome have been described, specific ligand(s) of NLRP3 and its mechanism of activation remain largely unknown. We performed a proteomics screen using co-immunoprecipitation (IP) and mass spectrometry to identify cellular proteins that bind NLRP3. Using this screen, we identified multiple NLRP3 interactors, including a family of solute carrier (SLC) proteins that localize to the inner mitochondrial membrane. Co-IP experiments verified that four of these proteins, namely SLC25A1, a citrate transporter, SLC25A6, an ADP/ATP translocase, SLC25A11, a 2-oxoglutarate/malate carrier, and SLC25A13, a calcium-dependent glutamate transporter, specifically interact with NLRP3. Because of its linkage with known metabolic disease, we further assessed the role of SCL25A13 in inflammasome function. When ectopically expressed, SLC25A13 enhanced IL-1β release from cells, while CRISPR/Cas9 knockout of SLC25A13 from THP-1 macrophages partially abrogated NLRP3-dependent pyroptosis. Our studies reveal a novel role for mitochondrial SLC25 proteins in regulation of the NLRP3 inflammasome. |
| Databáze: | OpenAIRE |
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