The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc Journal Article


Authors: Dong, H.; Adams, N. M.; Xu, Y.; Cao, J.; Allan, D. S. J.; Carlyle, J. R.; Chen, X.; Sun, J. C.; Glimcher, L. H.
Article Title: The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc
Abstract: 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 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-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 IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α−/− NK cells. Like c-Myc, IRE1α-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1α-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
Journal Title: Nature Immunology
Volume: 20
Issue: 7
ISSN: 1529-2908
Publisher: Nature Publishing Group  
Date Published: 2019-07-01
Start Page: 865
End Page: 878
Language: English
DOI: 10.1038/s41590-019-0388-z
PUBMED: 31086333
PROVIDER: scopus
PMCID: PMC6588410
DOI/URL:
Notes: Article -- Export Date: 1 July 2019 -- Source: Scopus
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MSK Authors
  1. Joseph C Sun
    71 Sun
  2. Nicholas M Adams
    13 Adams
  3. Yichi Xu
    2 Xu