Immunobiology and Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA.
Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA.
Cell Mol Immunol. 2022 Jun;19(6):687-701. doi: 10.1038/s41423-022-00852-7. Epub 2022 Mar 23.
The RNA helicase DHX15 is widely expressed in immune cells and traditionally thought to be an RNA splicing factor or a viral RNA sensor. However, the role of DHX15 in NK-cell activities has not been studied thus far. Here, we generated Dhx15-floxed mice and found that conditional deletion of Dhx15 in NK cells (Ncr1Dhx15 mice) resulted in a marked reduction in NK cells in the periphery and that the remaining Dhx15-deleted NK cells failed to acquire a mature phenotype. As a result, Dhx15-deleted NK cells exhibited profound defects in their cytolytic functions. We also found that deletion of Dhx15 in NK cells abrogated their responsiveness to IL-15, which was associated with inhibition of IL-2/IL-15Rβ (CD122) expression and IL-15R signaling. The defects in Dhx15-deleted NK cells were rescued by ectopic expression of a constitutively active form of STAT5. Mechanistically, DHX15 did not affect CD122 mRNA splicing and stability in NK cells but instead facilitated the surface expression of CD122, likely through interaction with its 3'UTR, which was dependent on the ATPase domain of DHX15 rather than its splicing domain. Collectively, our data identify a key role for DHX15 in regulating NK-cell activities and provide novel mechanistic insights into how DHX15 regulates the IL-15 signaling pathway in NK cells.
DHX15 是一种 RNA 解旋酶，广泛表达于免疫细胞中，传统上被认为是一种 RNA 剪接因子或病毒 RNA 传感器。然而，DHX15 在 NK 细胞活性中的作用迄今尚未研究。在这里，我们生成了 Dhx15 基因敲除小鼠，并发现 NK 细胞中 Dhx15 的条件性缺失（Ncr1Dhx15 小鼠）导致外周血中 NK 细胞明显减少，并且剩余的 Dhx15 缺失的 NK 细胞未能获得成熟表型。结果，Dhx15 缺失的 NK 细胞在细胞毒性功能上存在严重缺陷。我们还发现，NK 细胞中 Dhx15 的缺失消除了它们对 IL-15 的反应性，这与 IL-2/IL-15Rβ（CD122）表达和 IL-15R 信号的抑制有关。通过异位表达组成型激活形式的 STAT5，可挽救 Dhx15 缺失的 NK 细胞的缺陷。从机制上讲，DHX15 不影响 NK 细胞中 CD122 mRNA 的剪接和稳定性，而是促进 CD122 的表面表达，可能通过与 3'UTR 的相互作用来实现，这依赖于 DHX15 的 ATP 酶结构域，而不是其剪接结构域。总之，我们的数据确定了 DHX15 在调节 NK 细胞活性中的关键作用，并为 DHX15 如何调节 NK 细胞中的 IL-15 信号通路提供了新的机制见解。
