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

EMBO J. 2021 Jul 1;40(13):e106272. doi: 10.15252/embj.2020106272.

Gang Pei ¹, Joanna Zyla ¹ ², Lichun He ³ ⁴, Pedro Moura-Alves ¹ ⁵, Heidrun Steinle ⁶, Philippe Saikali ¹, Laura Lozza ¹, Natalie Nieuwenhuizen ¹, January Weiner ¹, Hans-Joachim Mollenkopf ⁷, Kornelia Ellwanger ⁶, Christine Arnold ⁶, Mojie Duan ³ ⁴, Yulia Dagil ⁸, Mikhail Pashenkov ⁸, Ivo Gomperts Boneca ⁹ ¹⁰ ¹¹, Thomas A Kufer ⁶, Anca Dorhoi ¹² ¹³, Stefan He Kaufmann ¹ ¹⁴

Affiliations

1 Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
2 Department of Data Science and Engineering, Silesian University of Technology, Gliwice, Poland.
3 State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, China.
4 University of Chinese Academy of Sciences, Beijing, China.
5 Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
6 Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
7 Microarray Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
8 Institute of Immunology of the Federal Medical-Biological Agency of Russia, Moscow, Russia.
9 Institut Pasteur, Department of Microbiology, Biology and Genetics of the Bacterial Cell Wall, Paris, France.
10 CNRS UMR2001, Integrative and Molecular Microbiology, Paris, France.
11 INSERM, Équipe AVENIR, Paris, France.
12 Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.
13 Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany.
14 Hagler Institute for Advanced Study at Texas A&M University, College Station, TX, USA.

PMID: 33942347 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.

Keywords

NOD-like receptors; NOD1/2; cellular homeostasis; inflammation; sphingolipid metabolism.

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