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A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation

The enzyme NDPK-D promotes changes in mitochondrial function that support inflammasome activation. An energetic checkpoint for inflammasomes Intracellular bacterial pathogens elicit inflammatory responses through inflammasomes, which are primed by a TLR-mediated inflammatory stimulus. Ernst et al. showed that the mitochondrial enzyme nucleoside diphosphate kinase D (NDPK-D) coordinates a metabolic checkpoint that ensures a robust response to the bacterial product LPS in mouse macrophages. This enzyme was necessary for the switch from aerobic to glycolytic metabolism that supported transcriptional responses to TLR-dependent priming. NDPK-D also promoted the synthesis of mitochondrial DNA and the exposure of the phospholipid cardiolipin on the mitochondrial surface, both of which contribute to inflammasome activation. Mice lacking NDPK-D were protected from LPS-induced septic shock. Thus, NDPK-D plays a key role in coordinating priming signals with the changes in mitochondrial function that are critical for inflammasome activation. 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.