A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation.
Orna ErnstJing SunBin LinBalaji BanothMichael G DorringtonJonathan LiangBenjamin SchwarzKaitlin A StrombergSamuel KatzSharat J VayttadenClinton J BradfieldNadia SlepushkinaChristopher M RiceEugen C BuehlerJaspal S KhillanDaniel W McVicarCatharine M BosioClare E BryantFayyaz S SutterwalaScott E MartinMadhu Lal-NagIain D C FraserPublished in: Science signaling (2021)
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.
Keyphrases
- inflammatory response
- lps induced
- toll like receptor
- lipopolysaccharide induced
- reactive oxygen species
- mitochondrial dna
- genome wide
- oxidative stress
- copy number
- nuclear factor
- transcription factor
- dna damage
- cell death
- diabetic rats
- gene expression
- physical activity
- tyrosine kinase
- microbial community
- cell cycle
- protein kinase
- drug delivery
- high glucose
- heat shock