Cellular stress promotes NOD1/2‐dependent inflammation via the endogenous metabolite sphingosine‐1‐phosphate

Gang Pei,Ivo Gomperts Boneca,Thomas A Kufer,Hans‐Joachim Mollenkopf,Yulia Dagil,January Weiner,Philippe Saikali,Joanna Zyla,Laura Lozza,Mojie Duan,Pedro Moura‐Alves,Heidrun Steinle,Kornelia Ellwanger,Stefan He Kaufmann,Natalie Nieuwenhuizen,Anca Dorhoi,Christine Arnold,Lichun He,Mikhail Pashenkov

doi:10.15252/embj.2020106272

Abstract

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine‐1‐phosphate (S1P). Unlike peptidoglycan sensing via the leucine‐rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF‐κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.

Highlights

Nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) are intracellular pattern recognition receptors that activate innate immune responses by sensing bacterial peptidoglycans (Caruso et al, 2014; Philpott et al, 2014)
We observed that induction of IL6 and IL8 expression and production correlated with NOD1/2 expression, without considerable differences of cell death in association with NOD1 or NOD2 expression (Fig 1A–D and Appendix Fig S1D–G)
We conclude that perturbation of cellular homeostasis induces specific NOD1/2-dependent pro-inflammatory signaling

Summary

Introduction

Nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) are intracellular pattern recognition receptors that activate innate immune responses by sensing bacterial peptidoglycans (Caruso et al, 2014; Philpott et al, 2014). In addition to well-established roles in bacterial sensing, both NOD1 and NOD2 modulate immune responses to a broad range of peptidoglycan-free microbes, such as respiratory syncytial virus (Sabbah et al, 2009), vesicular stomatitis virus (Sabbah et al, 2009), influenza A virus (Lupfer et al, 2014), human cytomegalovirus (Fan et al, 2016), hepatitis C virus (Vegna et al, 2016), Plasmodium berghei (Finney et al, 2009), Plasmodium falciparum (Corbett et al, 2015), and Trypanosoma cruzi (Silva et al, 2010). Chemical- or infection-induced endoplasmic reticulum (ER) stress triggers NOD1/2-mediated inflammation, as well (Keestra-Gounder et al, 2016). Whether NOD1/2 detect other types of cellular stress and what enables these receptors to sense such diverse stimuli remain unknown

Methods

Results

Conclusion