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

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 media...

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Bibliographic Details
Published in:Frontiers in immunology 2019-07, Vol.10, p.1495-1495
Main Authors: Chapman, Thomas P, Corridoni, Daniele, Shiraishi, Seiji, Pandey, Sumeet, Aulicino, Anna, Wigfield, Simon, do Carmo Costa, Maria, Thézénas, Marie-Laëtitia, Paulson, Henry, Fischer, Roman, Kessler, Benedikt M, Simmons, Alison
Format: Article
Language:English
Subjects:
ataxin 3
Ataxin-3 - immunology
Ataxin-3 - metabolism
Cell Respiration
HEK293 Cells
Humans
Immunity, Innate
Immunology
innate immnuity
metabolism
Mitochondria - metabolism
Myeloid Cells - immunology
Myeloid Cells - metabolism
Nod2
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
TLR2
Toll-Like Receptor 2 - immunology
Toll-Like Receptor 2 - metabolism
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Summary: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.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2019.01495