In all organisms, the innate immune system defends against pathogens through basal expression of molecules that provide critical barriers to invasion and inducible expression of effectors that combat infection. The adenosine deaminase that act on RNA (ADAR) family of RNA-binding proteins has been reported to influence innate immunity in metazoans. However, studies on the susceptibility of ADAR mutant animals to infection are largely lacking. Here, by analyzing adr-1 and adr-2 null mutants in well-established slow-killing assays, we find that both Caenorhabditis elegans ADARs are important for organismal survival to gram-negative and gram-positive bacteria, all of which are pathogenic to humans. Furthermore, our high-throughput sequencing and genetic analysis reveal that ADR-1 and ADR-2 function in the same pathway to regulate collagen expression. Consistent with this finding, our scanning electron microscopy studies indicate adr-1;adr-2 mutant animals also have altered cuticle morphology prior to pathogen exposure. Our data uncover a critical role of the C. elegans ADAR family of RNA-binding proteins in promoting cuticular collagen expression, which represents a new post-transcriptional regulatory node that influences the extracellular matrix. In addition, we provide the first evidence that ADAR mutant animals have altered susceptibility to infection with several opportunistic human pathogens, suggesting a broader role of ADARs in altering physical barriers to infection to influence innate immunity.

中文翻译：

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ADAR 调节角质层胶原表达并促进病原体感染的存活

在所有生物体中，先天免疫系统通过分子的基础表达来防御病原体，这些分子提供了入侵的关键屏障和对抗感染的效应子的诱导表达。据报道，作用于 RNA 结合蛋白的 RNA (ADAR) 家族的腺苷脱氨酶会影响后生动物的先天免疫。然而，关于 ADAR 突变动物对感染的易感性的研究却很缺乏。在这里，通过在成熟的慢杀试验中分析 adr-1 和 adr-2 无效突变体，我们发现秀丽隐杆线虫 ADAR 对于革兰氏阴性菌和革兰氏阳性菌的有机体生存都很重要，所有这些细菌都对革兰氏阴性菌和革兰氏阳性菌具有致病性。人类。此外，我们的高通量测序和遗传分析表明，ADR-1 和 ADR-2 在同一途径中发挥作用来调节胶原蛋白表达。与这一发现一致，我们的扫描电子显微镜研究表明 adr-1;adr-2 突变动物在接触病原体之前也改变了角质层形态。我们的数据揭示了秀丽隐杆线虫 ADAR 家族的 RNA 结合蛋白在促进角质层胶原表达中的关键作用，这代表了影响细胞外基质的新转录后调节节点。此外，我们提供了第一个证据，表明 ADAR 突变动物改变了对几种机会性人类病原体感染的易感性，这表明 ADAR 在改变感染的物理屏障以影响先天免疫方面具有更广泛的作用。