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

• DOI: 10.1126/scisignal.abe0387
• Publication Date: 2021-08-03T19:15:10Z
• Authors: Orna Ernst; Jing Sun; Bin Lin; Balaji Banoth; Michael G. Dorrin...; Jonathan Liang; Benjamin Schwarz; Kaitlin A. Stromberg; Samuel Katz; Sharat J. Vayttaden; Clinton J. Bradfield; Nadia Slepushkina; Christopher M. Rice; Eugen Buehler; Jaspal S. Khillan; Daniel W. McVicar; Catharine M. Bosio; Clare E. Bryant; Fayyaz S. Sutterwala; Scott E. Martin; Madhu Lal-Nag; Iain D. C. Fraser
• Keywords: Nucleoside-diphosphate kinase

Noncanonical inflammasome activation by cytosolic lipopolysaccharide (LPS) is a critical component of the host response to Gram-negative bacteria. Cytosolic LPS recognition in macrophages preceded Toll-like receptor (TLR) priming signal required induce transcription components and facilitate metabolic reprograming that fuels inflammatory response. Using genome-scale arrayed siRNA screen find regulators mouse macrophages, we identified mitochondrial enzyme nucleoside diphosphate kinase D (NDPK-D) as regulator both noncanonical canonical inflammasomes. NDPK-D was for DNA synthesis cardiolipin exposure on surface signals mediated TLRs, deficient had multiple defects LPS-induced activation. In addition, recruitment TNF receptor-associated factor 6 (TRAF6) mitochondria, which reactive oxygen species (ROS) production reprogramming supported TLR-induced gene program. knockout mice were protected from shock, consistent with decreased ROS attenuated glycolytic commitment during priming. Our findings suggest that, microbial challenge, NDPK-D-dependent TRAF6 triggers an energetic fitness checkpoint engage maintain transcriptional program necessary