Nutrient Sensing by the Intestinal Epithelium Orchestrates Mucosal Antimicrobial Defense via Translational Control of Hes1
Nutrient Sensing by the Intestinal Epithelium Orchestrates Mucosal Antimicrobial Defense via Translational Control of Hes1
复制标题
肠上皮细胞的营养感应通过 Hes1 的翻译控制协调粘膜抗菌防御
DOI：
10.1016/j.chom.2019.03.012
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发表时间：
2019-05-08
影响因子：
30.3
通讯作者：
Hu, Xiaoyu
中科院分区：
文献类型：
--
作者：
Liang, Shaonan;Guo, Xue-Kun;Hu, Xiaoyu
代谢程序和宿主防御是高度整合的，以确保在压力期间适当的免疫反应。作为这些反应的核心，mTOR通过感知和整合环境线索来调节免疫功能，但这些系统如何在肠道表面协调仍不清楚。我们表明，抗菌肽α-防御素是功能上持续的营养剥夺，因为调节防御素加工酶MMP 7的微生物和宿主衍生的因素。与其他抗菌肽不同，MMP 7a-防御素轴在营养波动期间保持活性，提供针对肠道病原体的必要保护。持续的Mmp 7表达需要微生物群，并且在肠上皮细胞中转录抑制因子Hes 1减弱后，通过转录激活因子Atoh 1的去抑制介导。Hes 1水平通过mTOR调节，并通过免疫控制，构成代谢-翻译-转录环。通过提供营养来破坏这个循环，矛盾的是会损害抗菌防御。总之，这些结果揭示了一个调节电路，夫妇主机营养状况上皮抗菌免疫。
Metabolic programs and host defense are highly integrated to ensure proper immune responses during stress. Central to these responses, mTOR regulates immune functions by sensing and integrating environmental cues, yet how these systems are coordinated at the intestinal surface remains undefined. We show that the antimicrobial peptide a-defensin is functionally sustained during nutrient deprivation because of regulation of the defensin-processing enzyme MMP7 by microbiota-and host-derived factors. Unlike other antimicrobial peptides, the MMP7a- defensin axis remains active during nutrient fluctuations, providing essential protection against enteric pathogens. Sustained Mmp7 expression requires the microbiota and is mediated by de-repression of the transcription activator Atoh1 upon attenuation of the transcriptional repressor Hes1 in intestinal epithelial cells. Hes1 levels are regulated via mTOR and controlled translationally, constituting a metabolism-translation-transcription loop. Disrupting this loop by supplying nutrients paradoxically compromises antibacterial defense. Together, these results uncover a regulatory circuit that couples host nutrient status to epithelial antimicrobial immunity.