NAGK

如果细菌进入宿主体内，先天免疫系统往往只需要几分钟就能识别出它们是外来的，并启动免疫防御。识别细菌细胞壁成分的免疫系统受体在这个过程中起着核心作用。 如果细菌进入宿主体内，先天免疫系统往往只需要几分钟就能识别出它们是外来的，并启动免疫防御。识别细菌细胞壁成分的免疫系统受体在这个过程中起着核心作用。一种重要的免疫刺激性细胞壁成分是胞壁酰二肽（muramyl dipeptide, MDP），它被受体NOD2识别。在一项新的研究中，来自德国马克斯-普朗克生物化学研究所和慕尼黑大学的研究人员发现了这一重要过程中一个以前未知的关键中间步骤。相关研究结果于2022年8月25日在线发表在Nature期刊上，论文标题为“Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation”。 受体NOD2主要由免疫细胞和肠道粘膜细胞产生。当被分子MDP激活时，它引发了炎症反应，阻止细菌进入肠壁。为了研究哪些基因参与这一信号通路，这些作者在体外培养的人类细胞中进行了广泛的基因筛选。令他们惊讶的是，他们发现一个编码酶NAGK的基因发挥了关键作用。NAGK是一种激酶，即一种可以将磷酸基团转移到其他分子的酶。 论文通讯作者、慕尼黑大学免疫学者Veit Hornung说，“为了让NOD2识别它的靶分子MDP，它必须首先被NAGK转化为它的磷酸化形式，我们能够通过随后的分子生物学和生物化学实验来证实这一点。这完全出乎意料。” 单倍体基因筛选揭示了NOD2的调控因子，图片来自Nature, 2022, doi:10.1038/s41586-022-05125-x。 NAGK的这一作用以前是未知的，并且与文献中已经描述的该酶在糖代谢中的功能无关。然而，这些作者确信，这与该酶在细菌中的原始功能十分吻合，它在细菌细胞壁的循环利用中发挥着重要作用。在整个进化过程中，NAGK一直保存在缺乏细胞壁的有机体中，因此指出了它在其他功能中的作用。 这项新发现也可能与炎症性肠病（包括克罗恩病和溃疡性结肠炎）的致病机制有关，因为NOD2基因的突变特别经常与克罗恩病（Crohn's disease）有关。论文第一作者、慕尼黑大学的Che Stafford说，“这项新的研究导致了一个令人兴奋的问题：NAGK的缺失或失活是否会导致炎症性肠病？”（生物谷 Bioon.com） 参考资料： Che A. Stafford et al. Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature, 2022, doi:10.1038/s41586-022-05125-x.

Immunologists have identified an important intermediate step in innate immune defense. If bacteria enter the body, it often takes just a few minutes for the innate immune system to recognise them as foreign and set the immune defence in motion. Receptors of the immune system that recognise bacterial cell wall components play a central role in this process. An important immune stimulatory cell wall component is the molecule muramyl dipeptide (MDP), which is recognised by the receptor NOD2. A team led by LMU immunologist Veit Hornung has now discovered a previously unknown crucial intermediate step in this important process, as the scientists report in the journal Nature. The receptor NOD2 is mainly produced by immune cells and cells of the intestinal mucosa. When activated by the molecule MDP, it triggers inflammatory responses that, among other things, prevent bacteria from entering the intestinal wall. To investigate which genes are involved in this signalling pathway, the researchers conducted an extensive genetic screen in cultured human cells. To their surprise, they found that a gene for the enzyme NAGK plays a crucial role. NAGK is a so-called kinase, an enzyme that can transfer a phosphoryl group to other molecules. "For NOD2 to identify its target molecule MDP, it must first be converted by NAGK into its phosphorylated form, as we were able to show through subsequent molecular biological and biochemical investigations," says Veit Hornung. "This was totally unexpected." This role of NAGK was previously unknown and is independent of the enzyme's function in sugar metabolism already described in the literature. However, the researchers are convinced that it corresponds well with the enzyme's original function in bacteria, where it plays an important role in recycling the bacterial cell wall. Throughout evolution, NAGK has been preserved in organisms that lack a cell wall, therefore pointing towards its role in other functions. The new findings could also be relevant to the mechanisms of inflammatory bowel disease, as mutations in the NOD2 gene are particularly frequently associated with Crohn's disease. "This work leads to the exciting question, does the absent or inactivation of NAGK lead to inflammatory bowel disease?" says Che Stafford, first author of the study.