Title | The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Dong H, Adams NM, Xu Y, Cao J, Allan DSJ, Carlyle JR, Chen X, Sun JC, Glimcher LH |
Journal | Nat Immunol |
Volume | 20 |
Issue | 7 |
Pagination | 865-878 |
Date Published | 2019 07 |
ISSN | 1529-2916 |
Keywords | Animals, Biomarkers, Cell Survival, Cytotoxicity, Immunologic, Endoplasmic Reticulum Stress, Endoribonucleases, Gene Expression Regulation, Genes, myc, Host-Pathogen Interactions, Humans, Immunity, Killer Cells, Natural, Lymphocyte Activation, Melanoma, Experimental, Mice, Mice, Knockout, Mitochondria, Oxidative Phosphorylation, Protein-Serine-Threonine Kinases, Signal Transduction, X-Box Binding Protein 1 |
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. |
DOI | 10.1038/s41590-019-0388-z |
Alternate Journal | Nat. Immunol. |
PubMed ID | 31086333 |
PubMed Central ID | PMC6588410 |
Grant List | R01 AI100874 / AI / NIAID NIH HHS / United States R37 CA228304 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R00 AI085034 / AI / NIAID NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States F30 AI136239 / AI / NIAID NIH HHS / United States P30 CA006516 / CA / NCI NIH HHS / United States R01 AI130043 / AI / NIAID NIH HHS / United States |
Submitted by bel2021 on December 2, 2019 - 10:24am