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.
Original language | English (US) |
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Pages (from-to) | 687-701 |
Number of pages | 15 |
Journal | Cellular and Molecular Immunology |
Volume | 19 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2022 |
Keywords
- DEAH-box helicase 15 (DHX15)
- Homeostasis
- IL-15 signaling pathway
- Innate immunity
- Natural killer (NK) cells
- Killer Cells, Natural/metabolism
- Animals
- Signal Transduction
- Interleukin-15
- RNA Helicases/genetics
- Mice
ASJC Scopus subject areas
- Infectious Diseases
- Immunology and Allergy
- Immunology