The IL-15–AKT–XBP1s signaling pathway contributes to effector functions and survival in human NK cells

• Published in: Nature immunology Vol. 20; no. 1; pp. 10 - 17
• Main Authors: Wang, Yufeng, Zhang, Yibo, Yi, Ping, Dong, Wenjuan, Nalin, Ansel P., Zhang, Jianying, Zhu, Zheng, Chen, Lichao, Benson, Don M., Mundy-Bosse, Bethany L., Freud, Aharon G., Caligiuri, Michael A., Yu, Jianhua
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2019; Nature Publishing Group
• Subjects: 631/250; 631/250/127; 631/250/2504; 631/250/262; AKT protein; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cell Survival; Cells, Cultured; Cellular signal transduction; Cytokines; Cytolytic activity; Cytotoxicity, Immunologic; Gene Expression Regulation; Genes; Granzyme B; Granzymes - genetics; Granzymes - metabolism; Humans; Immunology; Infectious Diseases; Interleukin 15; Interleukin-15 - metabolism; Interleukins; Killer cells; Killer Cells, Natural - immunology; Kinases; Letter; Leukemia; Natural killer cells; Phosphorylation; Protein Binding; Protein folding; Protein kinases; Protein Stability; Protein-serine/threonine kinase; Proto-Oncogene Proteins c-akt - metabolism; Serine; Signal Transduction; T-Box Domain Proteins - metabolism; Transcription (Genetics); Transcription factors; Ubiquitination; Unfolded Protein Response; X-Box Binding Protein 1 - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-018-0265-1

Interleukin 15 (IL-15) is one of the most important cytokines that regulate the biology of natural killer (NK) cells
1
. Here we identified a signaling pathway—involving the serine-threonine kinase AKT and the transcription factor XBP1s, which regulates unfolded protein response genes
2
,
3
—that was activated in response to IL-15 in human NK cells. IL-15 induced the phosphorylation of AKT, which led to the deubiquitination, increased stability and nuclear accumulation of XBP1s protein. XBP1s bound to and recruited the transcription factor T-BET to the gene encoding granzyme B, leading to increased transcription. XBP1s positively regulated the cytolytic activity of NK cells against leukemia cells and was also required for IL-15-mediated NK cell survival through an anti-apoptotic mechanism. Thus, the newly identified IL-15–AKT–XBP1s signaling pathway contributes to enhanced effector functions and survival of human NK cells.
Yu and colleagues show that the transcription factor XBP1s positively regulates the cytolytic activity of human NK cells and is required for the IL-15-mediated survival of NK cells.