RNA helicases play critical roles in various biological processes, including serving as viral RNA sensors in innate immunity. Here, we find that RNA helicase DEAH-box helicase 15 (DHX15) is essential for type I interferon (IFN-I, IFN-β), type III IFN (IFN-λ3), and inflammasome-derived cytokine IL-18 production by intestinal epithelial cells (IECs) in response to poly I:C and RNA viruses with preference of enteric RNA viruses, but not DNA virus. Importantly, we generate IEC-specific Dhx15-knockout mice and demonstrate that DHX15 is required for controlling intestinal inflammation induced by enteric RNA virus rotavirus in suckling mice and reovirus in adult mice in vivo, which owes to impaired IFN-β, IFN-λ3, and IL-18 production in IECs from Dhx15-deficient mice. Mechanistically, DHX15 interacts with NLRP6 to trigger NLRP6 inflammasome assembly and activation for inducing IL-18 secretion in IECs. Collectively, our report reveals critical roles for DHX15 in sensing enteric RNA viruses in IECs and controlling intestinal inflammation.

RNA 解旋酶在各种生物过程中发挥着关键作用，包括在先天免疫中充当病毒 RNA 传感器。在这里，我们发现 RNA 解旋酶 DEAH-box 解旋酶 15 (DHX15) 对于 I 型干扰素 (IFN-I、IFN-β)、III 型干扰素 (IFN-λ3) 和炎症小体衍生的细胞因子 IL-18 的产生至关重要。肠上皮细胞 (IEC) 对 Poly I:C 和 RNA 病毒的反应，优先考虑肠道 RNA 病毒，但不反应 DNA 病毒。重要的是，我们生成了 IEC 特异性Dhx15敲除小鼠，并证明 DHX15 是控制乳鼠肠道 RNA 病毒轮状病毒和成年小鼠体内呼肠孤病毒引起的肠道炎症所必需的，这是由于 IFN-β、IFN-λ3 受损、 Dhx15缺陷小鼠 IEC 中 IL-18 的产生。从机制上讲，DHX15 与 NLRP6 相互作用，触发 NLRP6 炎性体组装和激活，从而诱导 IEC 中的 IL-18 分泌。总的来说，我们的报告揭示了 DHX15 在感知 IEC 中肠道 RNA 病毒和控制肠道炎症方面的关键作用。