小柯机器人

德国慕尼黑大学Veit Hornung团队发现，NAGK对胞壁酰肽的磷酸化是NOD2激活所需。2022年8月24日，《自然》杂志在线发表了这项成果。

研究人员表示，细菌细胞壁成分提供了各种独特的分子结构，被先天免疫系统的模式识别受体（PRR）检测为非自我。大多数细菌物种形成的细胞壁由肽聚糖（PGN）组成，这是一种由交替的氨基糖组成的聚合结构，形成由短肽交联的链状物。胞壁酰二肽（MDP）作为肽聚糖的最小免疫原性成分已被充分报道。MDP被细胞膜上的含核苷酸结合的寡头结构蛋白2（NOD2）所感知。一旦接触，它就会触发促炎症基因的表达，这种功能对维持健康的肠道屏障功能至关重要。

研究人员使用正向遗传筛选来确定了MDP检测所需的因素，并确定N-乙酰葡糖胺激酶（NAGK）对MDP的免疫刺激活性至关重要。NAGK在免疫细胞中广泛表达，以前曾被描述为对己胺生物合成挽救途径的贡献。从机制上讲，NAGK在NOD2的上游发挥作用，直接将MDP的N-乙酰氨基甲酸分子在其C6位置的羟基处磷酸化，产生6-O-磷酸MDP。NAGK磷酸化的MDP，而不是未修饰的MDP，构成了NOD2的激动剂。缺少NAGK的小鼠巨噬细胞完全缺乏对MDP的感应。这些结果揭示了氨基糖代谢和对细菌细胞壁的先天免疫之间的联系。

附：英文原文

Title: Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation

Author: Stafford, Che A., Gassauer, Alicia-Marie, de Oliveira Mann, Carina C., Tanzer, Maria C., Fessler, Evelyn, Wefers, Benedikt, Nagl, Dennis, Kuut, Gunnar, Sulek, Karolina, Vasilopoulou, Catherine, Schwojer, Sophia J., Wiest, Andreas, Pfautsch, Marie K., Wurst, Wolfgang, Yabal, Monica, Frhlich, Thomas, Mann, Matthias, Gisch, Nicolas, Jae, Lucas T., Hornung, Veit

Issue&Volume: 2022-08-24

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 peptidoglycan1,2,3. 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.

DOI: 10.1038/s41586-022-05125-x

Source: https://www.nature.com/articles/s41586-022-05125-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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