Has our knowledge of mammalian innate immunity already reached its asymptote? π€
As we are pleased to report today in @Nature, NOD quite yet ... (1).
nature.com
As we are pleased to report today in @Nature, NOD quite yet ... (1).
nature.com
Bacterial cell walls yield an abundance of PAMPs that are recognized as non-self by various PRRs. One prominent PRR is the cytosolic sensor NOD2, which has been shown to recognize degradation products of peptidoglycan that forms the "mesh" of the prokaryotic cell wall (2).
The minimal motif recognized by NOD2 is muramyl dipeptide, indeed one of the first PAMPs to be fully chemically synthesized.
Although NOD2 signaling is well characterized, we performed a comprehensive forward genetic screen to map all genes required for MDP recognition (3).
Although NOD2 signaling is well characterized, we performed a comprehensive forward genetic screen to map all genes required for MDP recognition (3).
Doing so, we found almost all known positive regulators of NOD2 signaling, including NOD2 itself, as well as an additional gene that we did not have on our list. This was N-acetyl-D-glucosamine kinase (NAGK), an amino sugar kinase we had never heard of before (4).
NAGK-KO cells showed a complete loss of MDP-dependent NOD2 activation and further studies alluded to a role upstream of NOD2. NAGK deficiency also blunted the response towards complex peptidoglycan preps, indicating that NAGK is generally required to detect muramyl peptides (5).
Long story short β we then found that NAGK phosphorylates the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position. The thus-generated 6-O-phospho-MDP (but not unmodified MDP) thereby constitutes a potent agonist for NOD2 (6).
Next to various cell lines, also primary cells (bone marrow derived macrophages) from Nagk-deficient mice showed a complete loss of proinflammatory gene expression after MDP stimulation, whereas other PRR signaling pathways were not affected (7).
Please see the open access paper for all the details ... (8).
This study was a tremendous collaborative effort led by the great Che Stafford @che_stafford who was assisted by @AliciaGassauer, Dennis Nagel, @GunnarKuut, Sophia Schwojer, Andreas Wiest from @hornung_lab - @OliveiraMann - @MariaTanzer2 and Karolina Sulek, Catherine Vasilopoulou
and @labs_mann from @MPI_Biochem - Evelyn Fessler and @TheJaeLab - Benedikt Wefers and Wolfgang Wurst @HelmholtzMunich - Marie Pfautsch and @MonicaYabal - Thomas FrΓΆhlich - Nicolas Gisch @FZBorstel
A big thank you to our funding sources @dfg_public and @ERC_Research and our institute @GeneCenter_LMU @LMU_Muenchen
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