Original Research ARTICLE
Ataxin-3 links NOD2 and TLR2 mediated innate immune sensing and metabolism in myeloid cells
- 1University of Oxford, United Kingdom
- 2University of Michigan, United States
- 3University of Oxford, United Kingdom
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, Metabolism, Innate immnuity, ataxin 3
Received: 02 Apr 2019;
Accepted: 14 Jun 2019.
Edited by:Hannes Stockinger, Medical University of Vienna, Austria
Reviewed by:Guntram A. Grassl, Hannover Medical School, Germany
Jaya Talreja, School of Medicine, Wayne State University, United States
Copyright: © 2019 Chapman, Corridoni, Shiraishi, Pandey, Aulicino, Wigfield, do Carmo Costa, Thézénas, Paulson, Fischer, Kessler and Simmons. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Alison Simmons, University of Oxford, Oxford, OX1 2JD, England, United Kingdom, firstname.lastname@example.org