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Nat Immunol. 2019 May 13. doi: 10.1038/s41590-019-0388-z. [Epub ahead of print]

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

Dong H1,2,3, Adams NM4,5, Xu Y6, Cao J7,8,9, Allan DSJ10, Carlyle JR11,12, Chen X7,8,9, Sun JC4,5,13, Glimcher LH14,15,16.

Author information

1
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Medicine Brigham and Women's Hospital, Boston, MA, USA.
3
Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA.
4
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
8
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
9
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
10
National Heart Lung and Blood Institute, National Institute of Health, Bethesda, MD, USA.
11
Department of Immunology, University of Toronto, Toronto, Onatario, Canada.
12
Sunnybrook Research Institute, Toronto, Ontario, Canada.
13
Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
14
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. laurie_glimcher@dfci.harvard.edu.
15
Department of Medicine Brigham and Women's Hospital, Boston, MA, USA. laurie_glimcher@dfci.harvard.edu.
16
Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA. laurie_glimcher@dfci.harvard.edu.

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.

PMID:
31086333
DOI:
10.1038/s41590-019-0388-z

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