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The RNA helicase DHX15 is a critical regulator of natural killer-cell homeostasis and functions

Cellular & Molecular Immunology volume 19, pages 687–701 (2022)Cite this article

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Abstract

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 (Ncr1CreDhx15fl/fl 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.

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Acknowledgements

We thank Professor Eric Vivier at the Innate Pharma Research Labs in France for the generous gift of Ncr1Cre mice. We acknowledge the excellent services obtained from the flow cytometry core and Comparative Medicine Program at Houston Methodist Hospital in Houston, Texas. This project was supported by National Institutes of Health grants (R01AI080779 and R01 A1155488).

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Authors and Affiliations

  1. Immunobiology and Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Texas Medical Center, Houston, TX, USA

    Guangchuan Wang, Xiang Xiao, Yixuan Wang, Xiufeng Chu, Yaling Dou, Laurie J. Minze, Rafik M. Ghobrial, Zhiqiang Zhang & Xian C. Li

  2. Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA

    Rafik M. Ghobrial, Zhiqiang Zhang & Xian C. Li

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  1. Guangchuan Wang
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GW designed and performed the experiments and analyzed the data. XX helped with FACS and mouse irradiation. LM provided operational support. XX, YW, XC, RG, and YD performed some experiments and provided helpful discussions. ZZ helped revise the paper. XCL supervised the studies and wrote the paper.

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Correspondence to Xian C. Li.

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Wang, G., Xiao, X., Wang, Y. et al. The RNA helicase DHX15 is a critical regulator of natural killer-cell homeostasis and functions. Cell Mol Immunol 19, 687–701 (2022). https://doi.org/10.1038/s41423-022-00852-7

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