TY  - JOUR
AU  - Stafford, Che A
AU  - Gassauer, Alicia-Marie
AU  - de Oliveira Mann, Carina C
AU  - Tanzer, Maria C
AU  - Fessler, Evelyn
AU  - Wefers, Benedikt
AU  - Nagl, Dennis
AU  - Kuut, Gunnar
AU  - Sulek, Karolina
AU  - Vasilopoulou, Catherine
AU  - Schwojer, Sophia J
AU  - Wiest, Andreas
AU  - Pfautsch, Marie K
AU  - Wurst, Wolfgang
AU  - Yabal, Monica
AU  - Fröhlich, Thomas
AU  - Mann, Matthias
AU  - Gisch, Nicolas
AU  - Jae, Lucas T
AU  - Hornung, Veit
TI  - Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation.
JO  - Nature 
VL  - 609
IS  - 7927
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DZNE-2022-01440
SP  - 590 - 596
PY  - 2022
N1  - CC BY: https://creativecommons.org/licenses/by/4.0/
AB  - 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.
KW  - Acetylmuramyl-Alanyl-Isoglutamine: chemistry
KW  - Acetylmuramyl-Alanyl-Isoglutamine: immunology
KW  - Acetylmuramyl-Alanyl-Isoglutamine: metabolism
KW  - Acetylmuramyl-Alanyl-Isoglutamine: pharmacology
KW  - Animals
KW  - Bacteria: chemistry
KW  - Bacteria: immunology
KW  - Cell Wall: chemistry
KW  - Hexosamines: biosynthesis
KW  - Immunity, Innate
KW  - Macrophages: enzymology
KW  - Macrophages: immunology
KW  - Mice
KW  - Nod2 Signaling Adaptor Protein: agonists
KW  - Nod2 Signaling Adaptor Protein: metabolism
KW  - Peptidoglycan: chemistry
KW  - Peptidoglycan: immunology
KW  - Phosphorylation
KW  - Phosphotransferases (Alcohol Group Acceptor): deficiency
KW  - Phosphotransferases (Alcohol Group Acceptor): genetics
KW  - Phosphotransferases (Alcohol Group Acceptor): metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9477735
C6  - pmid:36002575
DO  - DOI:10.1038/s41586-022-05125-x
UR  - https://pub.dzne.de/record/165135
ER  -