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

Nat Immunol. 2019 Jul;20(7):865-878. doi: 10.1038/s41590-019-0388-z. Epub 2019 May 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cytotoxicity, Immunologic
  • Endoplasmic Reticulum Stress / genetics*
  • Endoribonucleases / genetics*
  • Gene Expression Regulation*
  • Genes, myc*
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity / genetics*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Lymphocyte Activation / immunology
  • Melanoma, Experimental
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Oxidative Phosphorylation
  • Protein Serine-Threonine Kinases / genetics*
  • Signal Transduction
  • X-Box Binding Protein 1 / metabolism


  • Biomarkers
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases