165135 20230915090606.0 pmc:PMC9477735 pmc 10.1038/s41586-022-05125-x doi pmid:36002575 pmid 0028-0836 ISSN 1476-4687 ISSN altmetric:134936564 altmetric DZNE-2022-01440 English 500 Stafford, Che A 0 Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. London [u.a.] 2022 Nature Publ. Group article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1664543975_12116 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote CC BY: https://creativecommons.org/licenses/by/4.0/ 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Acetylmuramyl-Alanyl-Isoglutamine: chemistry MeSH Acetylmuramyl-Alanyl-Isoglutamine: immunology MeSH Acetylmuramyl-Alanyl-Isoglutamine: metabolism MeSH Acetylmuramyl-Alanyl-Isoglutamine: pharmacology MeSH Animals MeSH Bacteria: chemistry MeSH Bacteria: immunology MeSH Cell Wall: chemistry MeSH Hexosamines: biosynthesis MeSH Immunity, Innate MeSH Macrophages: enzymology MeSH Macrophages: immunology MeSH Mice MeSH Nod2 Signaling Adaptor Protein: agonists MeSH Nod2 Signaling Adaptor Protein: metabolism MeSH Peptidoglycan: chemistry MeSH Peptidoglycan: immunology MeSH Phosphorylation MeSH Phosphotransferases (Alcohol Group Acceptor): deficiency MeSH Phosphotransferases (Alcohol Group Acceptor): genetics MeSH Phosphotransferases (Alcohol Group Acceptor): metabolism MeSH Gassauer, Alicia-Marie 1 de Oliveira Mann, Carina C 2 Tanzer, Maria C 0000-0002-4657-9869 3 Fessler, Evelyn 4 Wefers, Benedikt P:(DE-2719)2810988 5 dzne Nagl, Dennis 6 Kuut, Gunnar 7 Sulek, Karolina 8 Vasilopoulou, Catherine 9 Schwojer, Sophia J 0000-0002-1747-4144 10 Wiest, Andreas 0000-0003-2525-6304 11 Pfautsch, Marie K 12 Wurst, Wolfgang P:(DE-2719)2000028 13 dzne Yabal, Monica 0000-0003-3495-7671 14 Fröhlich, Thomas 0000-0002-4709-3211 15 Mann, Matthias 0000-0003-1292-4799 16 Gisch, Nicolas 0000-0003-3260-5269 17 Jae, Lucas T 0000-0002-3531-1760 18 Hornung, Veit 0000-0002-4150-194X 19 10.1038/s41586-022-05125-x Vol. 609, no. 7927, p. 590 - 596 PERI:(DE-600)1413423-8 7927 590 - 596 Nature <London> 609 2022 0028-0836 OpenAccess http://pub.dzne.de/record/165135/files/DZNE-2022-01440.pdf OpenAccess pdfa http://pub.dzne.de/record/165135/files/DZNE-2022-01440.pdf?subformat=pdfa oai:pub.dzne.de:165135 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2810988 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 13 P:(DE-2719)2000028 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2022 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-01-27 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-01-27 DBCoverage StatID:(DE-HGF)1210 StatID Index Chemicus 2021-01-27 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-01-27 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)1200 StatID Chemical Reactions 2021-01-27 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC JCR StatID:(DE-HGF)0100 StatID NATURE : 2021 2022-11-29 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-29 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-29 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2022-11-29 Peer Review StatID:(DE-HGF)0030 StatID ASC 2022-11-29 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-29 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-29 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-29 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-29 DBCoverage StatID:(DE-HGF)1040 StatID Zoological Record 2022-11-29 DBCoverage StatID:(DE-HGF)1060 StatID Current Contents - Agriculture, Biology and Environmental Sciences 2022-11-29 DBCoverage StatID:(DE-HGF)1150 StatID Current Contents - Physical, Chemical and Earth Sciences 2022-11-29 IF >= 60 StatID:(DE-HGF)9960 StatID NATURE : 2021 2022-11-29 I:(DE-2719)1140001 AG Wurst Genome Engineering 0 journal VDB UNRESTRICTED I:(DE-2719)1140001 FullTexts