ABSTRACT

The production of natural antimicrobial peptides has emerged as an important mechanism of innate immunity in animals. Defensins, members of a large family of antimicrobial peptides, have been suggested as effector molecules in host defence against bacteria, fungi, protozoa and enveloped viruses. However, the molecular mechanism underlying defensin upregulation in bacterial infection remains poorly understood. The modification of mRNA by N6-adenosine methylation (m⁶A) on internal bases influences gene expression in eukaryotes. Here, we show that β-defensin production triggered by Enterotoxigenic Escherichia coli K88 (E. coli K88) infection is controlled by the cellular m⁶A methyltransferase METTL3. Adding back with METTL3 robustly stimulated the re-expression of defensin, which further supports the conclusion. Furthermore, using a MeRIP-seq approach, we identified a functional connection between m⁶A dependent GPR161 signalling and the expression of defensins. Mechanistically, we found that the transcription factor FOXO6 interacted with METTL3 to trigger the transcription of GPR161 and the subsequent regulation of β-defensin expression. The study has shed light on the mechanisms by which enterotoxigenic Escherichia coli infection promotes enteric defensin expression.

摘要

天然抗菌肽的产生已成为动物先天免疫的重要机制。防御素是抗微生物肽大家族的成员，已被建议作为宿主防御细菌、真菌、原生动物和包膜病毒的效应分子。然而，细菌感染中防御素上调的分子机制仍然知之甚少。N6-腺苷甲基化 (m ⁶ A) 对内部碱基的 mRNA 修饰影响真核生物中的基因表达。在这里，我们表明由产肠毒素大肠杆菌K88（大肠杆菌K88）感染触发的 β-防御素生产受细胞 m ⁶甲基转移酶 METTL3。加入 METTL3 有力地刺激了防御素的重新表达，这进一步支持了结论。此外，使用 MeRIP-seq 方法，我们确定了 m ⁶ A 依赖性 GPR161 信号与防御素表达之间的功能联系。从机制上讲，我们发现转录因子 FOXO6 与 METTL3 相互作用以触发 GPR161 的转录和随后对 β-防御素表达的调节。该研究阐明了产肠毒素大肠杆菌感染促进肠道防御素表达的机制。