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Stafford, C.A.* ; Gassauer, A.M.* ; de Oliveira Mann, C.C.* ; Tanzer, M.C.* ; Fessler, E.* ; Wefers, B. ; Nagl, D.* ; Kuut, G.* ; Sulek, K.* ; Vasilopoulou, C.G.* ; Schwojer, S.J.* ; Wiest, A.* ; Pfautsch, M.K.* ; Wurst, W. ; Yabal, M.* ; Fröhlich, T.* ; Mann, M.* ; Gisch, N.* ; Jae, L.T.* ; Hornung, V.*

Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation.

Nature 609, 590-596 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan (PGN), a polymeric structure comprising alternating amino sugars that form strands cross-linked by short peptides. Muramyl dipeptide (MDP) has been well documented as a minimal immunogenic component of peptidoglycan1-3. MDP is sensed by the cytosolic nucleotide-binding oligomerization domain-containing protein 24 (NOD2). Upon engagement, it triggers pro-inflammatory gene expression, and this functionality is of critical importance in maintaining a healthy intestinal barrier function5. Here, using a forward genetic screen to identify factors required for MDP detection, we identified N-acetylglucosamine kinase (NAGK) as being essential for the immunostimulatory activity of MDP. NAGK is broadly expressed in immune cells and has previously been described to contribute to the hexosamine biosynthetic salvage pathway6. Mechanistically, NAGK functions upstream of NOD2 by directly phosphorylating the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP-but not unmodified MDP-constitutes an agonist for NOD2. Macrophages from mice deficient in NAGK are completely deficient in MDP sensing. These results reveal a link between amino sugar metabolism and innate immunity to bacterial cell walls.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 609, Issue: 7927, Pages: 590-596 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
Grants Helmholtz Association
Ludwig-Maximilians-Universitat Munchen
Max-Planck-Gesellschaft
Else Kroner-Fresenius-Stiftung
Deutsche Forschungsgemeinschaft
H2020 Marie Skłodowska-Curie Actions
Horizon 2020 Framework Programme