The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells-猫眼课题宝

DOI：

10.1073/pnas.2017432118

发表时间：

2021-01

期刊：

Proceedings of the National Academy of Sciences

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Yalong Wang;Kaixin He;B. Sheng;Xuqiu Lei;Wanyin Tao;Xiaoliang Zhu;Zheng Wei;Rongjie Fu;Anlei Wang;Shengdan Bai;Zhao Zhang;N. Hong;Chaoyang Ye;Ye Tian;Jun Wang;Mingsong Li;Kaiguang Zhang;Lin Li;Hua Yang;Hua-Bing Li;R. Flavell;Shu Zhu

RNA解旋酶在多种生物过程中发挥着重要作用。然而，由于完全缺乏RNA解旋酶的小鼠的致死率，体内数据很少。在这里，我们产生了在肠道中条件敲除DEAD-box解旋酶15 （Dhx15）的小鼠，我们在Paneth细胞中发现了抗菌肽(AMP) α-防御素的特异性缺陷。此外，我们发现肠道dhx15特异性缺失导致小鼠对肠道细菌感染的易感性以及葡聚糖硫酸钠诱导的结肠炎。在人类中，我们也发现溃疡性结肠炎患者Dhx15蛋白水平降低。RNA解旋酶在RNA剪接和编辑等多种重要的生物学过程中发挥作用。最近的体外研究表明，RNA解旋酶参与对病毒的免疫反应，作为病毒RNA传感器或免疫信号转接器。然而，由于RNA解旋酶完全敲除小鼠的致死率，仍然缺乏体内数据来支持RNA解旋酶的组织或细胞特异性功能；此外，关于解旋酶的抗菌作用也缺乏证据。在这里，我们通过产生肠上皮细胞（IEC）特异性Dhx15缺陷的小鼠（Dhx15 f/f Villin1-cre, Dhx15ΔIEC）来研究Dhx15在肠道抗菌反应中的体内作用。由于Paneth细胞α-防御素分泌受损，这些小鼠易受肠道细菌啮齿柠檬酸杆菌（C. rod）感染。此外，由于肠道菌群失调，Paneth细胞特异性Dhx15 （Dhx15 f/f Defensinα6-cre, Dhx15ΔPaneth）缺失的小鼠更容易发生DSS（葡聚糖硫酸钠）诱导的结肠炎（Dhx15ΔIEC小鼠）。在人类中，在溃疡性结肠炎（UC）患者中发现Dhx15蛋白水平降低。综上所述，我们的研究结果确定了wnt诱导的Paneth细胞α-防御素的关键调节因子，并为其在抗菌反应和肠道炎症中的作用提供了新的见解。

Significance RNA helicases play critical roles in multiple biological processes. However, little in vivo data are available because of the lethality of mice completely deficient in RNA helicases. Here, we generate mice with conditional knockout of DEAD-box Helicase 15 (Dhx15) in the intestine, in which we found a specific defect in antimicrobial peptide (AMP) α-defensins in Paneth cells. Additionally, we found that Dhx15-specific depletion in the intestine leads to susceptibility to enteric bacterial infection as well as dextran sulfate sodium-induced colitis in mice. In humans, we also found reduced protein levels of Dhx15 in ulcerative colitis patients. RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases. Here, we investigated the in vivo role of Dhx15 in intestinal antibacterial responses by generating mice that were intestinal epithelial cell (IEC)-specific deficient for Dhx15 (Dhx15 f/f Villin1-cre, Dhx15ΔIEC). These mice are susceptible to infection with enteric bacteria Citrobacter rodentium (C. rod), owing to impaired α-defensin production by Paneth cells. Moreover, mice with Paneth cell-specific depletion of Dhx15 (Dhx15 f/f Defensinα6-cre, Dhx15ΔPaneth) are more susceptible to DSS (dextran sodium sulfate)-induced colitis, which phenocopy Dhx15ΔIEC mice, due to the dysbiosis of the intestinal microbiota. In humans, reduced protein levels of Dhx15 are found in ulcerative colitis (UC) patients. Taken together, our findings identify a key regulator of Wnt-induced α-defensins in Paneth cells and offer insights into its role in the antimicrobial response as well as intestinal inflammation.

The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells

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