Mgat1-dependent N-glycosylation of membrane components primes Drosophila melanogaster blood cells for the cellular encapsulation response.
Mgat1-dependent N-glycosylation of membrane components primes Drosophila melanogaster blood cells for the cellular encapsulation response.
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DOI：
10.1371/journal.ppat.1002819
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Schlenke TA
中科院分区：
文献类型：
--
作者：
Mortimer NT;Kacsoh BZ;Keebaugh ES;Schlenke TA
在自然界中，果蝇的幼虫通常会被寄生蜂感染，因此已经进化出强大的免疫反应来对抗黄蜂感染。在这种反应中，苍蝇免疫细胞在黄蜂卵周围形成多层胶囊，导致寄生虫死亡。这种包封反应背后的许多分子机制在人类免疫反应中是保守的。我们的研究结果表明，蛋白质N-糖基化，一种常见的蛋白质翻译后修饰的人类免疫蛋白，可能是这样一个保守的机制。我们发现，果蝇免疫细胞膜蛋白的N-糖基化在一个时间特异性的方式黄蜂感染后。此外，我们已经确定了八个基因的突变编码酶的N-糖基化途径，降低苍蝇抵抗黄蜂感染。更具体地说，黄蜂感染后免疫细胞中蛋白质N-糖基化的丧失导致形成有缺陷的胶囊，这些胶囊随着时间的推移而解体，从而不能成功阻止黄蜂发育。有趣的是，我们还发现，一种果蝇寄生蜂，Leptopilina victoriae，靶向蛋白质N-糖基化作为其毒力机制的一部分，并且N-糖基化酶的过表达可以赋予对这种黄蜂物种的抗性，否则易受感染的苍蝇。两者合计，这些研究结果表明，蛋白质N-糖基化是果蝇细胞包裹的关键球员，并建议这种反应可能提供一种新的模型来研究蛋白质糖基化在免疫中的保守作用。果蝇等生物长期以来一直被用作理解人类生物学复杂方面的模型系统。对果蝇抗微生物免疫的研究已经导致了对人类先天免疫机制的鉴定，例如使用Toll样受体识别抗原和启动体液免疫应答。苍蝇和人类也被较大的寄生虫感染，它们对这些寄生虫产生基于血细胞的免疫反应，但细胞免疫的遗传基础特征很差。在自然界中，苍蝇经常被寄生蜂感染，寄生蜂在苍蝇幼虫中产卵，诱导苍蝇的细胞免疫反应。苍蝇血细胞包围黄蜂卵，形成一个紧密连接的胶囊，导致卵在一个称为包囊的过程中死亡，这类似于人类肉芽肿的形成。在这项研究中，我们确定了八个新的基因，这些基因对包囊很重要。这些基因是N-糖基化途径的一部分，我们发现，如果血细胞表面的蛋白质没有N-糖基化，黄蜂卵周围的胶囊就不能合并成一个紧密的胶囊，从而使黄蜂逃脱。有趣的是，我们还发现了一种破坏N-糖基化的黄蜂，这样它就可以逃避封装反应。我们的工作可能为更好地理解N-糖基化在人类免疫中的作用提供了一个模型。
In nature, larvae of the fruitfly Drosophila melanogaster are commonly infected by parasitoid wasps, and so have evolved a robust immune response to counter wasp infection. In this response, fly immune cells form a multilayered capsule surrounding the wasp egg, leading to death of the parasite. Many of the molecular mechanisms underlying this encapsulation response are conserved with human immune responses. Our findings suggest that protein N-glycosylation, a common protein post-translational modification of human immune proteins, may be one such conserved mechanism. We found that membrane proteins on Drosophila immune cells are N-glycosylated in a temporally specific manner following wasp infection. Furthermore we have identified mutations in eight genes encoding enzymes of the N-glycosylation pathway that decrease fly resistance to wasp infection. More specifically, loss of protein N-glycosylation in immune cells following wasp infection led to the formation of defective capsules, which disintegrated over time and were thereby unsuccessful at preventing wasp development. Interestingly, we also found that one species of Drosophila parasitoid wasp, Leptopilina victoriae, targets protein N-glycosylation as part of its virulence mechanism, and that overexpression of an N-glycosylation enzyme could confer resistance against this wasp species to otherwise susceptible flies. Taken together, these findings demonstrate that protein N-glycosylation is a key player in Drosophila cellular encapsulation and suggest that this response may provide a novel model to study conserved roles of protein glycosylation in immunity. Organisms such as the fruitfly Drosophila melanogaster have long been used as model systems to understand complex aspects of human biology. Work on Drosophila antimicrobial immunity has led to identification of mechanisms underlying human innate immunity, such as the use of Toll-like receptors for recognizing antigen and initiating humoral immune responses. Flies and humans are also infected by larger parasites against which they mount immune blood-cell based responses, but the genetic basis for cellular immunity is poorly characterized. In nature, flies are often infected by parasitoid wasps that lay their eggs in fly larvae, inducing a cellular immune response in the flies. Fly blood cells surround the wasp egg and form a tightly connected capsule leading to death of the egg in a process called encapsulation, which is similar to human granuloma formation. In this study we identified eight new genes that are important for encapsulation. These genes are part of the N-glycosylation pathway, and we found that without N-glycosylation of proteins on blood cell surfaces, capsules surrounding wasp eggs cannot consolidate into a tight capsule, allowing the wasps to escape. Interestingly, we also found a wasp that disrupts N-glycosylation so that it can evade the encapsulation response. Our work may provide a model to better understand the role of N-glycosylation in human immunity.
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影响因子：
4.8
作者：
Léonard, R;Rendic, D;Altmann, F
通讯作者：
Altmann, F
DOI：
10.1073/pnas.57.2.359
发表时间：
1967-01-01
影响因子：
11.1
作者：
BURGER, MM;GOLDBERG, AR
通讯作者：
GOLDBERG, AR
影响因子：
4.4
作者：
Baycin-Hizal, Deniz;Tian, Yuan;Betenbaugh, Michael J.
通讯作者：
Betenbaugh, Michael J.
DOI：
10.1038/nri2417
发表时间：
2008-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.8
作者：
Labrosse, C;Staslak, K;Poirie, M
通讯作者：
Poirie, M