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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 (IRE1?) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1?-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? downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1?-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1?-/- NK cells. Like c-Myc, IRE1?-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1?-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.

SUBMITTER: Dong H

PROVIDER: S-EPMC6588410 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Dong Han H Adams Nicholas M NM Xu Yichi Y Cao Jin J Allan David S J DSJ Carlyle James R JR Chen Xi X Sun Joseph C JC Glimcher Laurie H LH

Nature immunology 20190513 7

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 ...[more]

PMID: 31086333

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Project description:The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1?-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1? protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1? appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1? antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC-alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1? is activated in IBV-infected cells and serves as a survival factor during coronavirus infection.Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1?), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1? is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis.

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

Publications

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

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