Journal
NATURE IMMUNOLOGY
Volume 20, Issue 7, Pages 865-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-019-0388-z
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Funding
- Dana-Farber Cancer Institute
- Helen Gurley Brown Presidential Initiative Award (Dana-Farber Cancer Institute)
- Ludwig Center for Cancer Immunotherapy
- American Cancer Society
- Burroughs Wellcome Fund
- NIH [1 R37 CA228304-01]
- MSTP Grant from the National Institute of General Medical Sciences of the NIH [T32GM007739]
- National Institue of Allergy and Infectious Diseases of the NIH [F30 AI136239]
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Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1 alpha) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1 alpha-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1 alpha downregulated c-Myc, and NK cells with c-Myc haplo-insufficency phenocopied IRE1 alpha-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1 alpha(-/-) NK cells. Like c-Myc, IRE1 alpha-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1 alpha-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.
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