Recognition of Bacterial Signal Peptides by Mammalian Formyl Peptide Receptors A NEW MECHANISM FOR SENSING PATHOGENS
Recognition of Bacterial Signal Peptides by Mammalian Formyl Peptide Receptors A NEW MECHANISM FOR SENSING PATHOGENS
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DOI：
10.1074/jbc.m114.626747
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发表时间：
2015-03-20
影响因子：
4.8
通讯作者：
Zufall, Frank
中科院分区：
文献类型：
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作者：
Bufe, Bernd;Schumann, Timo;Zufall, Frank
背景：甲酰肽受体（FPRs）的功能还不完全清楚。结果如下：我们报告了细菌信号肽作为哺乳动物FPRs和先天免疫反应的有效激活剂的鉴定，并定义了FPR肽识别的关键特征。结论：这些发现确定了FPR激活的分子特征。重要性：甲酰肽受体（FPRs）是一种G蛋白偶联受体，在先天免疫反应中起化学引诱物受体的作用。在这里，我们进行系统的结构-功能分析FPR从六种哺乳动物的结构不同的FPR肽激动剂，并确定一组共同的保守激动剂的特性与病原体相关的分子模式的典型特征。在这些结果的指导下，我们发现通常用于跨细胞质膜转运蛋白的细菌信号肽是天然FPR激动剂的一个庞大家族。具有可变序列和长度的N-末端甲酰化信号肽片段在低纳摩尔浓度下激活人和小鼠FPR 1和FPR 2，从而将FPR 1和FPR 2确立为敏感和广泛的信号肽受体。犁鼻受体mFpr-rs 1及其序列同源物hFPR 3也与信号肽反应，但在信号肽识别中调节得更窄。此外，这里检查的所有信号肽作为先天免疫系统的有效激活剂起作用。它们在人类和小鼠白细胞中引起稳健的FPR依赖性钙动员，并触发一系列经典的先天防御机制，如活性氧物质的产生、金属蛋白酶释放和趋化性。因此，细菌信号肽构成一类新的免疫激活剂，可能有助于哺乳动物对细菌的免疫防御。这种进化上保守的检测机制将结构混杂与高特异性相结合，并能够区分细菌和真核生物的信号序列。至少有175，542个预测序列，细菌信号肽代表了目前已知的先天免疫系统中最大和结构上最异质的G蛋白偶联受体激动剂类别。
Background: The function of formyl peptide receptors (FPRs) is incompletely understood. Results: We report the identification of bacterial signal peptides as potent activators of mammalian FPRs and innate immune responses and define critical features underlying FPR peptide recognition. Conclusion: These findings identify a molecular signature for FPR activation. Significance: Our results define a novel mechanism for sensing bacteria.Formyl peptide receptors (FPRs) are G-protein-coupled receptors that function as chemoattractant receptors in innate immune responses. Here we perform systematic structure-function analyses of FPRs from six mammalian species using structurally diverse FPR peptide agonists and identify a common set of conserved agonist properties with typical features of pathogen-associated molecular patterns. Guided by these results, we discover that bacterial signal peptides, normally used to translocate proteins across cytoplasmic membranes, are a vast family of natural FPR agonists. N-terminally formylated signal peptide fragments with variable sequence and length activate human and mouse FPR1 and FPR2 at low nanomolar concentrations, thus establishing FPR1 and FPR2 as sensitive and broad signal peptide receptors. The vomeronasal receptor mFpr-rs1 and its sequence orthologue hFPR3 also react to signal peptides but are much more narrowly tuned in signal peptide recognition. Furthermore, all signal peptides examined here function as potent activators of the innate immune system. They elicit robust, FPR-dependent calcium mobilization in human and mouse leukocytes and trigger a range of classical innate defense mechanisms, such as the production of reactive oxygen species, metalloprotease release, and chemotaxis. Thus, bacterial signal peptides constitute a novel class of immune activators that are likely to contribute to mammalian immune defense against bacteria. This evolutionarily conserved detection mechanism combines structural promiscuity with high specificity and enables discrimination between bacterial and eukaryotic signal sequences. With at least 175,542 predicted sequences, bacterial signal peptides represent the largest and structurally most heterogeneous class of G-protein-coupled receptor agonists currently known for the innate immune system.