Extracellular matrix protein N-glycosylation mediates immune self-tolerance in Drosophila melanogaster.
Extracellular matrix protein N-glycosylation mediates immune self-tolerance in Drosophila melanogaster.
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DOI：
10.1073/pnas.2017460118
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发表时间：
2021-09-28
影响因子：
11.1
通讯作者：
Schlenke TA
中科院分区：
文献类型：
--
作者：
Mortimer NT;Fischer ML;Waring AL;Kr P;Kacsoh BZ;Brantley SE;Keebaugh ES;Hill J;Lark C;Martin J;Bains P;Lee J;Vrailas-Mortimer AD;Schlenke TA
免疫细胞区分自身组织与非自身病原体的能力是免疫的一个关键特征，允许反应针对入侵的病原体，同时保护免受自我导向的免疫损伤。先天免疫细胞对非我的识别已经得到了广泛的表征，但是允许自我识别和自我耐受的机制仍然在很大程度上未被探索。在这里，我们发现了一个自我耐受系统在果蝇，依赖于N-糖基化的细胞外基质蛋白：免疫活性受到抑制的自我信号的识别和收益时，遇到自己的组织丢失的自我信号。这使得宿主能够识别和保护自身组织，摧毁异常组织，并可能对逃避非自我识别系统的病原体做出反应。为了应对感染，宿主必须将病原体与自身组织区分开来。这允许针对病原体的免疫反应的精确靶向，并且还确保了自身耐受性，即宿主保护自身组织免受免疫损伤的能力。维持自身耐受性的一种方法是进化出一种自身信号，并抑制针对携带这种信号的组织的任何免疫反应。在这里，我们描述了果蝇tuSz 1突变株，它对自己的脂肪体产生异常的免疫反应。我们证明，这种自身免疫性是两个突变的结果：1）GCS 1基因的突变，破坏了覆盖脂肪体的细胞外基质蛋白的N-糖基化，2）果蝇Janus激酶直系同源物的突变，导致血细胞的早熟激活。我们的数据表明，N-聚糖连接到细胞外基质蛋白作为一个自我信号和激活的血细胞攻击缺乏这种信号的组织。这种无脊椎动物自我识别系统的简单性及其组成部分的普遍性表明它可能在动物中具有功能同源物。
The ability of immune cells to distinguish self tissue from nonself pathogens is a key characteristic of immunity, allowing responses to be targeted against invading pathogens while protecting against self-directed immune damage. The recognition of nonself by innate immune cells has been extensively characterized, but the mechanisms that allow for self recognition and self-tolerance remain largely unexplored. Here, we uncover a self-tolerance system in Drosophila that relies on the N-glycosylation of extracellular matrix proteins: immune activity is restrained by recognition of a self signal and proceeds when encountering self tissues missing the self signal. This allows the host to recognize and protect self tissues, destroy aberrant tissue, and, perhaps, respond to pathogens that evade nonself recognition systems. In order to respond to infection, hosts must distinguish pathogens from their own tissues. This allows for the precise targeting of immune responses against pathogens and also ensures self-tolerance, the ability of the host to protect self tissues from immune damage. One way to maintain self-tolerance is to evolve a self signal and suppress any immune response directed at tissues that carry this signal. Here, we characterize the Drosophila tuSz1 mutant strain, which mounts an aberrant immune response against its own fat body. We demonstrate that this autoimmunity is the result of two mutations: 1) a mutation in the GCS1 gene that disrupts N-glycosylation of extracellular matrix proteins covering the fat body, and 2) a mutation in the Drosophila Janus Kinase ortholog that causes precocious activation of hemocytes. Our data indicate that N-glycans attached to extracellular matrix proteins serve as a self signal and that activated hemocytes attack tissues lacking this signal. The simplicity of this invertebrate self-recognition system and the ubiquity of its constituent parts suggests it may have functional homologs across animals.
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影响因子：
4.7
作者：
Cvetko A;Kifer D;Gornik O;Klarić L;Visser E;Lauc G;Wilson JF;Štambuk T
通讯作者：
Štambuk T
影响因子：
1.2
作者：
Bach, Erika A.;Ekas, Laura A.;Baeg, Gyeong-Hun
通讯作者：
Baeg, Gyeong-Hun
影响因子：
2.9
作者：
Eslin, Patrice;Doury, Geraldine
通讯作者：
Doury, Geraldine
影响因子：
12.3
作者：
Cook RK;Christensen SJ;Deal JA;Coburn RA;Deal ME;Gresens JM;Kaufman TC;Cook KR
通讯作者：
Cook KR
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