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

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.

• Authors: Gang Pei, Joanna Zyla, Lichun He, Pedro Moura-Alves, Heidrun Steinle, Philippe Saikali, Laura Lozza, Natalie Nieuwenhuizen, January Weiner, Hans-Joachim Mollenkopf, Kornelia Ellwanger, Christine Arnold, Mojie Duan, Yulia Dagil, Mikhail Pashenkov, Ivo Gomperts Boneca, Thomas A Kufer, Anca Dorhoi, Stefan He Kaufmann
• Journal: The EMBO journal (EMBO J) Vol. 40 Issue 13 Pg. e106272 (07 01 2021) ISSN: 1460-2075 [Electronic] England
• PMID: 33942347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Lysophospholipids
• NF-kappa B
• NOD1 protein, human
• NOD2 protein, human
• Nod1 Signaling Adaptor Protein
• Nod2 Signaling Adaptor Protein
• Peptidoglycan
• sphingosine 1-phosphate
• Sphingosine

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Female
• HEK293 Cells
• HeLa Cells
• Humans
• Inflammation (metabolism)
• Lysophospholipids (metabolism)
• Mice
• NF-kappa B (metabolism)
• Nod1 Signaling Adaptor Protein (metabolism)
• Nod2 Signaling Adaptor Protein (metabolism)
• Peptidoglycan (metabolism)
• Signal Transduction (physiology)
• Sphingosine (analogs & derivatives, metabolism)
• THP-1 Cells