Frontiers in Immunology (Jul 2019)

Ataxin-3 Links NOD2 and TLR2 Mediated Innate Immune Sensing and Metabolism in Myeloid Cells

  • Thomas P. Chapman,
  • Daniele Corridoni,
  • Seiji Shiraishi,
  • Sumeet Pandey,
  • Anna Aulicino,
  • Simon Wigfield,
  • Maria do Carmo Costa,
  • Marie-Laëtitia Thézénas,
  • Henry Paulson,
  • Roman Fischer,
  • Benedikt M. Kessler,
  • Alison Simmons

DOI
https://doi.org/10.3389/fimmu.2019.01495
Journal volume & issue
Vol. 10

Abstract

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The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well-established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1α and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.

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