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

Front Immunol. 2019 Jul 19;10:1495. doi: 10.3389/fimmu.2019.01495. eCollection 2019.

Abstract

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.

Keywords: Nod2; TLR2; ataxin 3; innate immnuity; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxin-3 / immunology*
  • Ataxin-3 / metabolism
  • Cell Respiration
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Mitochondria / metabolism
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism*
  • Nod2 Signaling Adaptor Protein / immunology*
  • Nod2 Signaling Adaptor Protein / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / immunology
  • Protein Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / immunology*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
  • Signal Transduction
  • THP-1 Cells
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 2 / metabolism

Substances

  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Reactive Oxygen Species
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Protein Serine-Threonine Kinases
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • TBK1 protein, human
  • Ataxin-3