Aminopeptidase MNP-1 triggers intestine protease production by activating daf-16 nuclear location to degrade pore-forming toxins in Caenorhabditis elegans.
Aminopeptidase MNP-1 triggers intestine protease production by activating daf-16 nuclear location to degrade pore-forming toxins in Caenorhabditis elegans.
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氨肽酶MNP-1通过激活daf-16核定位来降解秀丽隐杆线虫中的成孔毒素，从而触发肠蛋白酶的产生。
DOI：
10.1371/journal.ppat.1011507
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发表时间：
2023-07
期刊：
影响因子：
6.7
通讯作者：
Peng, Donghai R.
中科院分区：
文献类型：
--
作者：
Chen, Feng;Pang, Cuiyun;Zheng, Ziqiang;Zhou, Wei;Guo, Zhiqing;Xiao, Danyang;Du, Hongwen;Bravo, Alejandra;Soberon, Mario R.;Sun, Ming R.;Peng, Donghai R.
成孔毒素（PFT）是病原体感染的有效工具。通过破坏上皮屏障并杀死免疫细胞，PFT 促进病原微生物在宿主体内的定植和繁殖。反过来，宿主会触发防御反应，例如胞吞作用、胞吐作用或自噬作用。苏云金芽孢杆菌 (Bt) 细菌产生 PFT，称为晶体蛋白 (Cry)，它会损害昆虫或线虫的肠道细胞，最终杀死它们。在昆虫中，氨肽酶 N (APN) 已被证明是 Cry 毒素的重要受体。在这里，以线虫秀丽隐杆线虫为模型，对 APN 基因家族进行了广泛的筛选，以分析这些蛋白在 Cry5Ba 对抗线虫的作用模式中的潜在作用。我们发现一种 APN，MNP-1，参与毒素防御反应，因为 mnp-1(ok2434) 突变体表现出 Cry5Ba 过敏表型。 mnp-1(ok2434) 突变体中的基因表达分析揭示了参与 Cry5Ba 降解的两个蛋白酶基因 F19C6.4 和 R03G8.6。最后，对参与 F19C6.4 和 R03G8.6 表达的转导途径的分析表明，暴露于 Cry5Ba 后，线虫通过激活 FOXO 转录因子 DAF-16 上调这两种蛋白酶基因，并将其转入细胞核。在 Cry5Ba 处理下，发现 DAF-16 的核位置依赖于 mnp-1。我们的工作提供了宿主针对肠道致病菌产生的 PFT 的新反应的证据，从而导致宿主肠道蛋白酶的激活，从而降解肠道中的 PFT。成孔毒素（PFT）在微生物病原体的发病机制中起着至关重要的作用。同时，宿主在细胞水平上介导不同的策略来抵抗PFT，如胞吞作用、胞吐作用、自噬和MAPK或炎性体信号通路。在这里，我们发现线虫秀丽隐杆线虫通过诱导显示核位置的 FOXO 转录因子 DAF-16 上调肠道蛋白酶，对诱导其蛋白水解的 PFT 做出反应。我们的研究结果表明，动物在 PFT 中毒后不仅在细胞水平上触发防御机制，而且还可以消除肠腔中的 PFT，这是动物抵抗 PFT（尤其是肠道细菌病原体产生的 PFT）的有效附加策略。由于 FOXO 转录因子 DAF-16 从线虫到哺乳动物都是保守的，因此通过调节肠道蛋白酶降解 PFT 可能是对抗细菌感染的常见防御策略。
Pore-forming toxins (PFTs) are effective tools for pathogens infection. By disrupting epithelial barriers and killing immune cells, PFTs promotes the colonization and reproduction of pathogenic microorganisms in their host. In turn, the host triggers defense responses, such as endocytosis, exocytosis, or autophagy. Bacillus thuringiensis (Bt) bacteria produce PFT, known as crystal proteins (Cry) which damage the intestinal cells of insects or nematodes, eventually killing them. In insects, aminopeptidase N (APN) has been shown to act as an important receptor for Cry toxins. Here, using the nematode Caenorhabditis elegans as model, an extensive screening of APN gene family was performed to analyze the potential role of these proteins in the mode of action of Cry5Ba against the nematode. We found that one APN, MNP-1, participate in the toxin defense response, since the mnp-1(ok2434) mutant showed a Cry5Ba hypersensitive phenotype. Gene expression analysis in mnp-1(ok2434) mutant revealed the involvement of two protease genes, F19C6.4 and R03G8.6, that participate in Cry5Ba degradation. Finally, analysis of the transduction pathway involved in F19C6.4 and R03G8.6 expression revealed that upon Cry5Ba exposure, the worms up regulated both protease genes through the activation of the FOXO transcription factor DAF-16, which was translocated into the nucleus. The nuclear location of DAF-16 was found to be dependent on mnp-1 under Cry5Ba treatment. Our work provides evidence of new host responses against PFTs produced by an enteric pathogenic bacterium, resulting in activation of host intestinal proteases that degrade the PFT in the intestine. Pore-forming toxins (PFTs) have a crucial role in the pathogenesis of microbial pathogens. Meanwhile, hosts mediate different strategies to resist PFTs at the cellular level, such as endocytosis, exocytosis, autophagy, and MAPK or inflammasome signaling pathways. Here we show that the nematode Caenorhabditis elegans respond to PFTs inducing their proteolysis by up regulating intestinal proteases through the induction of FOXO transcription factor DAF-16 that showed nuclear location. Our results indicate that animals not only trigger defense mechanisms after PFTs intoxication at the cellular level, but also could eliminate PFTs in the intestine lumen, an effective additional strategy for animals to resist PFTs, especially those produced by enteric bacterial pathogens. Since, the FOXO transcription factor DAF-16 is conserved from nematodes to mammals, it is possible that the degradation of PFT by modulating intestinal proteases may be a common defense strategy against bacterial infections.
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