Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties
Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties
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DOI：
10.4049/jimmunol.1701719
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发表时间：
2018-05-01
影响因子：
4.4
通讯作者：
Forsman, Huamei
中科院分区：
文献类型：
--
作者：
Gabl, Michael;Sundqvist, Martina;Forsman, Huamei
吞噬性嗜中性粒细胞表达甲酰肽受体（FPR; FPR 1和FPR 2），其明显识别以N-甲酰化甲硫氨酸（fMet）开始的肽。这是细菌代谢的标志;与原核生物类似，线粒体DNA编码蛋白质合成的起始氨基酸是fMet。具有N-末端fMet的线粒体隐蔽肽（mitocryptides; MCT）可以通过我们的先天免疫系统识别;然而，与我们对细菌代谢物的了解相反，对MCT的识别特征知之甚少。在这项研究中，我们确定了来自13个人类线粒体DNA编码蛋白的N末端的假定MCT的嗜中性粒细胞识别特征和功能输出。13种MCT中有6种可有效激活具有不同FPR识别特征的中性粒细胞：来自ND 3和ND 6的MCT对FPR 1具有受体偏好性;来自蛋白质ND 4、ND 5和细胞色素B的MCT偏好FPR 2; MCT-COX 1是一种FPR 1/FPR 2双重激动剂。来自ND 2和ND 4L的MCT是非常弱的中性粒细胞激活剂，而来自ND 1、ATP 6、ATP 8、COX 2和COX 3的MCT不发挥FPR激动或拮抗作用。此外，活化MCT异源脱敏IL-8 R，但引发对血小板活化因子受体激动剂的反应。更重要的是，我们的数据表明，MCT具有偏向信号传导特性，有利于激活产生超氧化物的NADPH氧化酶或募集β-抑制蛋白。总之，我们确定了几种新的FPR激活肽的序列存在于线粒体DNA编码蛋白的N末端，我们的数据阐明了中性粒细胞激活MCT的分子基础。
Phagocytic neutrophils express formyl peptide receptors (FPRs; FPR1 and FPR2) that distinctly recognize peptides starting with an N-formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA-encoded proteins is an fMet. Mitochondrial cryptic peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA-encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochrome b prefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of beta-arrestin. In summary, we identify several novel FPR-activating peptides with sequences present in the N termini of mitochondrial DNA-encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs.