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Ernst O, Sun J, Lin B, et al. A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation. Sci Signal. 2021;14(694)doi: 10.1126/scisignal.abe0387.
Ernst, O., Sun, J., Lin, B., Banoth, B., Dorrington, M. G., Liang, J., Schwarz, B., Stromberg, K. A., Katz, S., Vayttaden, S. J., Bradfield, C. J., Slepushkina, N., Rice, C. M., Buehler, E., Khillan, J. S., McVicar, D. W., Bosio, C. M., Bryant, C. E., Sutterwala, F. S., Martin, S. E., Lal-Nag, M., & Fraser, I. D. C. (2021). A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation. Science signaling, 14(694), . https://doi.org/10.1126/scisignal.abe0387
Ernst, Orna, et al. "A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation." Science signaling vol. 14,694 (2021). doi: https://doi.org/10.1126/scisignal.abe0387
Ernst O, Sun J, Lin B, Banoth B, Dorrington MG, Liang J, Schwarz B, Stromberg KA, Katz S, Vayttaden SJ, Bradfield CJ, Slepushkina N, Rice CM, Buehler E, Khillan JS, McVicar DW, Bosio CM, Bryant CE, Sutterwala FS, Martin SE, Lal-Nag M, Fraser IDC. A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation. Sci Signal. 2021 Aug 03;14(694). doi: 10.1126/scisignal.abe0387. PMID: 34344832.
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Sci Signal. 2021 Aug 03;14(694). doi: 10.1126/scisignal.abe0387.

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

Science signaling

Orna Ernst, Jing Sun, Bin Lin, Balaji Banoth, Michael G Dorrington, 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

Affiliations

  1. Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  2. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  3. Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.
  4. Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
  5. The Trans-NIH RNAi Facility, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA.
  6. Laboratory of Cancer Immunometabolism, National Cancer Institute, NIH, Frederick, MD 21702, USA.
  7. Mouse Genetics and Gene Modification Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  8. Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. [email protected].

PMID: 34344832 DOI: 10.1126/scisignal.abe0387

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.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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