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Cellular stress promotes NOD1/2‐dependent inflammation via the endogenous metabolite sphingosine‐1‐phosphate
Author(s) -
Pei Gang,
Zyla Joanna,
He Lichun,
MouraAlves Pedro,
Steinle Heidrun,
Saikali Philippe,
Lozza Laura,
Nieuwenhuizen Natalie,
Weiner January,
Mollenkopf HansJoachim,
Ellwanger Kornelia,
Arnold Christine,
Duan Mojie,
Dagil Yulia,
Pashenkov Mikhail,
Boneca Ivo Gomperts,
Kufer Thomas A,
Dorhoi Anca,
Kaufmann Stefan HE
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106272
Subject(s) - library science , biology , computer science
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.