Ataxin-3 links NOD2 and TLR2 mediated innate immune sensing and metabolism in myeloid cells

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-1 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.\n\nSignificance StatementIn recent years it has become clear that cross-talk between metabolic and immune pathways is central to the regulation of host defence. This interplay appears of particular importance in myeloid cells including dendritic cells and macrophages, but it is unclear how two of their key bacterial sensors NOD2 and TLR2 influence metabolism. Here, we define how NOD2/TLR2 signal in myeloid cells to drive optimal mitochondrial functioning required for bacterial destruction. We uncover a new role for Ataxin-3, a deubiquitinase required for non-selective autophagy, in this pathway. We provide a non-biased analysis of Ataxin-3 targets generating evidence for a role in deubiquitination of metabolic mediators during myeloid cell differentiation that will provide an important basis for further study.