Article ; Online: A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation.
2021 Volume 14, Issue 694
Abstract: Noncanonical inflammasome activation by cytosolic lipopolysaccharide (LPS) is a critical component of the host response to Gram-negative bacteria. Cytosolic LPS recognition in macrophages is preceded by a Toll-like receptor (TLR) priming signal required ... ...
| Abstract | Noncanonical inflammasome activation by cytosolic lipopolysaccharide (LPS) is a critical component of the host response to Gram-negative bacteria. Cytosolic LPS recognition in macrophages is preceded by a Toll-like receptor (TLR) priming signal required to induce transcription of inflammasome components and facilitate the metabolic reprograming that fuels the inflammatory response. Using a genome-scale arrayed siRNA screen to find inflammasome regulators in mouse macrophages, we identified the mitochondrial enzyme nucleoside diphosphate kinase D (NDPK-D) as a regulator of both noncanonical and canonical inflammasomes. NDPK-D was required for both mitochondrial DNA synthesis and cardiolipin exposure on the mitochondrial surface in response to inflammasome priming signals mediated by TLRs, and macrophages deficient in NDPK-D had multiple defects in LPS-induced inflammasome activation. In addition, NDPK-D was required for the recruitment of TNF receptor-associated factor 6 (TRAF6) to mitochondria, which was critical for reactive oxygen species (ROS) production and the metabolic reprogramming that supported the TLR-induced gene program. NDPK-D knockout mice were protected from LPS-induced shock, consistent with decreased ROS production and attenuated glycolytic commitment during priming. Our findings suggest that, in response to microbial challenge, NDPK-D-dependent TRAF6 mitochondrial recruitment triggers an energetic fitness checkpoint required to engage and maintain the transcriptional program necessary for inflammasome activation. |
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| MeSH term(s) | Animals ; Inflammasomes/genetics ; Inflammasomes/metabolism ; Lipopolysaccharides/metabolism ; Macrophages/metabolism ; Mice ; Mitochondria/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Nucleoside Diphosphate Kinase D/metabolism ; Reactive Oxygen Species/metabolism |
| Chemical Substances | Inflammasomes ; Lipopolysaccharides ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species ; Nucleoside Diphosphate Kinase D (EC 2.7.4.6) |
| Language | English |
| Publishing date | 2021-08-03 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2417226-1 |
| ISSN | 1937-9145 ; 1945-0877 |
| ISSN (online) | 1937-9145 |
| ISSN | 1945-0877 |
| DOI | 10.1126/scisignal.abe0387 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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