Palmitoylation of NOD1 and NOD2 is required for bacterial sensing
Palmitoylation of NOD1 and NOD2 is required for bacterial sensing
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细菌传感需要 NOD1 和 NOD2 的棕榈酰化
DOI：
10.1126/science.aau6391
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发表时间：
2019-10-25
期刊：
影响因子：
56.9
通讯作者：
Neculai, Dante
中科院分区：
文献类型：
--
作者：
Lu, Yan;Zheng, Yuping;Neculai, Dante
NOD需要S-棕榈酰化来发出信号。细胞内蛋白质的区室化对其功能至关重要。脂质分子的加入使蛋白质重新分布到细胞表面或膜结合的细胞器。Lu等人在转基因小鼠和组织培养细胞中工作，发现核苷酸寡聚化结构域样受体1和2（NOD 1和NOD 2），两种负责检测细菌产物的蛋白质，需要脂质修饰才能招募到细胞膜并发挥功能。特定的修饰，半胱氨酸巯基的棕榈酰化，是由酶ZDHHC 5介导的。ZDHHC 5的缺失或NOD 1和NOD 2中关键修饰残基的去除废除了它们的功能，损害了抗菌反应。NOD 2的人类变体显示棕榈酰化改变，这可能有助于解释许多炎症性疾病，如肠易激综合征。脂质化将NOD 1和NOD 2靶向到细菌传感的正确位置，并在NOD 2克罗恩病变体中发生改变。核苷酸寡聚化结构域（NOD）样受体1和2（NOD 1/2）是细胞内模式识别蛋白，其响应于与微生物相关的肽聚糖而激活免疫信号传导途径。募集到含有细菌的内体和其他细胞内膜是NOD 1/2信号传导所必需的，并且破坏膜定位的NOD 1/2突变与炎性肠病和其他炎性病症相关。然而，人们对这一招聘过程知之甚少。我们发现NOD 1/2 S-棕榈酰化是膜募集和免疫信号传导所必需的。ZDHHC 5被鉴定为负责这种关键的翻译后修饰的棕榈酰转移酶，并且发现NOD 2中的几种疾病相关突变与缺陷的S-棕榈酰化相关。因此，ZDHHC 5介导的NOD 1/2的S-棕榈酰化对于它们响应肽聚糖和产生有效免疫应答的能力至关重要。
NODs require S-palmitoylation to signal The compartmentalization of proteins within the cell is essential for their function. The addition of lipid molecules redistributes proteins to the cell surface or to membrane-bound organelles. Working in transgenic mice and in tissue cultured cells, Lu et al. found that nucleotide oligomerization domain–like receptors 1 and 2 (NOD1 and NOD2), two proteins responsible for detecting bacterial products, required lipid modifications for their recruitment to the cell membrane and function. The specific modification, palmitoylation at a cysteine thiol, was mediated by the enzyme ZDHHC5. Loss of ZDHHC5 or removal of key modification residues in NOD1 and NOD2 abolished their function, compromising antibacterial responses. Human variants of NOD2 display altered palmitoylation, which could help to explain many inflammatory conditions, such as irritable bowel syndrome. Science, this issue p. 460 Lipidation targets NOD1 and NOD2 to the right place for bacterial sensing and is altered in NOD2 Crohn’s disease variants. The nucleotide oligomerization domain (NOD)–like receptors 1 and 2 (NOD1/2) are intracellular pattern-recognition proteins that activate immune signaling pathways in response to peptidoglycans associated with microorganisms. Recruitment to bacteria-containing endosomes and other intracellular membranes is required for NOD1/2 signaling, and NOD1/2 mutations that disrupt membrane localization are associated with inflammatory bowel disease and other inflammatory conditions. However, little is known about this recruitment process. We found that NOD1/2 S-palmitoylation is required for membrane recruitment and immune signaling. ZDHHC5 was identified as the palmitoyltransferase responsible for this critical posttranslational modification, and several disease-associated mutations in NOD2 were found to be associated with defective S-palmitoylation. Thus, ZDHHC5-mediated S-palmitoylation of NOD1/2 is critical for their ability to respond to peptidoglycans and to mount an effective immune response.