Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation

Che A. Stafford, Alicia-Marie Gassauer, Carina C. Oliveira Mann, Maria C. Tanzer, Evelyn Fessler, Benedikt Wefers, Dennis Nagl, Gunnar Kuut, Karolina Sulek, Catherine Vasilopoulou, Sophia J. Schwojer, Andreas Wiest, Marie K. Pfautsch, Wolfgang Wurst, Monica Yabal, Thomas Fröhlich, Matthias Mann, Nicolas Gisch, Lucas T. Jae and Veit Hornung ()
Additional contact information
Che A. Stafford: Ludwig-Maximilians-Universität
Alicia-Marie Gassauer: Ludwig-Maximilians-Universität
Carina C. Oliveira Mann: Ludwig-Maximilians-Universität
Maria C. Tanzer: Max-Planck Institute of Biochemistry
Evelyn Fessler: Ludwig-Maximilians-Universität
Benedikt Wefers: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE)
Dennis Nagl: Ludwig-Maximilians-Universität
Gunnar Kuut: Ludwig-Maximilians-Universität
Karolina Sulek: Novo Nordisk Foundation Center for Protein Research (NNF-CPR)
Catherine Vasilopoulou: Max-Planck Institute of Biochemistry
Sophia J. Schwojer: Ludwig-Maximilians-Universität
Andreas Wiest: Ludwig-Maximilians-Universität
Marie K. Pfautsch: Technical University of Munich
Wolfgang Wurst: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE)
Monica Yabal: Technical University of Munich
Thomas Fröhlich: Ludwig-Maximilians-Universität
Matthias Mann: Max-Planck Institute of Biochemistry
Nicolas Gisch: Research Center Borstel, Leibniz Lung Center
Lucas T. Jae: Ludwig-Maximilians-Universität
Veit Hornung: Ludwig-Maximilians-Universität

Nature, 2022, vol. 609, issue 7927, 590-596

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-05125-x

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