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

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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
JournalCellular and Molecular Immunology
DOIs
StateAccepted/In press - 2022

Keywords

  • DEAH-box helicase 15 (DHX15)
  • Homeostasis
  • IL-15 signaling pathway
  • Innate immunity
  • Natural killer (NK) cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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