Marutani Takayuki, Hattori Tatsuya, Tsutsumi Koki, Koike Yusuke, Harada Akihiko, Noguchi Kosuke, Kiso Yoshiaki, Mukai Hidehito
Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
Biopolymers. 2016 Nov 4;106(4):580-7. doi: 10.1002/bip.22788.
Recently, much attention has been paid to "nonclassical" bioactive peptides, which are fragmented peptides simultaneously produced during maturation and degradation of various functional proteins. We identified many fragmented peptides derived from various mitochondrial proteins including mitocryptide-1 and mitocryptide-2 that efficiently activate neutrophils. These endogenous, functionally active, fragmented peptides are referred to as "cryptides." Among them, mitocryptide-2 is an N-formylated cryptide cleaved from mitochondrial cytochrome b that is encoded in mitochondrial DNA (mtDNA). It is known that 13 proteins encoded in mtDNA are translated in mitochondria as N-formylated forms, suggesting the existence of endogenous N-formylated peptides other than mitocryptide-2. Here, we investigated the effects of N-formylated peptides presumably cleaved from mtDNA-encoded proteins other than cytochrome b on the functions of neutrophilic cells to elucidate possible regulation by endogenous N-formylated cryptides. Four N-formylated cryptides derived from cytochrome c oxidase subunit I and NADH dehydrogenase subunits 4, 5, and 6 among 12 peptides from mtDNA-encoded proteins efficiently induced not only migration but also β-hexosaminidase release, which is an indicator of neutrophilic phagocytosis, in HL-60 cells differentiated into neutrophilic cells. These activities were comparable to or higher than those induced by mitocryptide-2. Although endogenous N-formylated peptides that are contained in mitochondrial damage-associated molecular patterns (DAMPs) have yet to be molecularly identified, they have been implicated in innate immunity. Thus, N-formylated cryptides including mitocryptide-2 are first-line candidates for the contents of mitochondrial DAMPs to promote innate immune responses. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 580-587, 2016.
最近，“非经典”生物活性肽备受关注，它们是在各种功能蛋白成熟和降解过程中同时产生的片段化肽。我们鉴定出许多源自各种线粒体蛋白的片段化肽，包括能有效激活中性粒细胞的线粒体隐肽 -1 和线粒体隐肽 -2。这些内源性、具有功能活性的片段化肽被称为“隐肽”。其中，线粒体隐肽 -2 是一种从线粒体细胞色素 b 切割而来的 N - 甲酰化隐肽，线粒体细胞色素 b 由线粒体 DNA（mtDNA）编码。已知 mtDNA 编码的 13 种蛋白质在线粒体中以 N - 甲酰化形式翻译，这表明除了线粒体隐肽 -2 之外还存在其他内源性 N - 甲酰化肽。在此，我们研究了可能从细胞色素 b 以外的 mtDNA 编码蛋白切割而来的 N - 甲酰化肽对嗜中性细胞功能的影响，以阐明内源性 N - 甲酰化隐肽可能的调节作用。在来自 mtDNA 编码蛋白的 12 种肽中，源自细胞色素 c 氧化酶亚基 I 以及 NADH 脱氢酶亚基 4、5 和 6 的四种 N - 甲酰化隐肽不仅能有效诱导 HL - 60 细胞分化为嗜中性细胞后的迁移，还能诱导 β - 己糖胺酶释放，β - 己糖胺酶释放是嗜中性吞噬作用的一个指标。这些活性与线粒体隐肽 -2 诱导的活性相当或更高。虽然线粒体损伤相关分子模式（DAMPs）中所含的内源性 N - 甲酰化肽尚未在分子水平上得到鉴定，但它们与先天免疫有关。因此，包括线粒体隐肽 -2 在内的 N - 甲酰化隐肽是促进先天免疫反应的线粒体 DAMPs 成分的首要候选者。© 2015 威利期刊公司。生物聚合物（肽科学）106: 580 - 587，2016。
