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Nat Commun. 2018 Dec 17;9(1):5340. doi: 10.1038/s41467-018-07758-x.

Stabilization of cytokine mRNAs in iNKT cells requires the serine-threonine kinase IRE1alpha.

Author information

1
Unit for Molecular Immunology and Inflammation, VIB Center for Inflammation Research, Technologiepark 927, 9052, Zwijnaarde (Ghent), Belgium.
2
Department of Rheumatology, Ghent University, Ghent University Hospital, Ghent, 9000, Belgium.
3
Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, 9000, Belgium.
4
Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Technologiepark 927, 9052, Zwijnaarde (Ghent), Belgium.
5
Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Technologiepark 927, 9052 Zwijnaarde (Ghent), Belgium.
6
Department of Respiratory Medicine, Ghent University, Ghent University Hospital, 9000, Ghent, Belgium.
7
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Kanazawa, 920-0856, Japan.
8
Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Technologiepark 927, 9052, Zwijnaarde (Ghent), Belgium.
9
Unit for Structural Biology, VIB Center for Inflammation Research, Technologiepark 927, 9052, Zwijnaarde, (Ghent), Belgium.
10
Department of Pulmonary Medicine, Ghent University, ErasmusMC, Rotterdam, 2040, Netherlands.
11
Laboratory of ER Stress and Inflammation, VIB Center for Inflammation Research, Technologiepark 927, 9052, Zwijnaarde (Ghent), Belgium.
12
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, 9000, Belgium.
13
Unit for Molecular Immunology and Inflammation, VIB Center for Inflammation Research, Technologiepark 927, 9052, Zwijnaarde (Ghent), Belgium. Dirk.Elewaut@ugent.be.
14
Department of Rheumatology, Ghent University, Ghent University Hospital, Ghent, 9000, Belgium. Dirk.Elewaut@ugent.be.

Abstract

Activated invariant natural killer T (iNKT) cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear. Here we show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), links key cellular processes required for iNKT cell effector functions in specific iNKT subsets, in which TCR-dependent activation of IRE1α is associated with downstream activation of p38 MAPK and the stabilization of preformed cytokine mRNAs. Importantly, genetic deletion of IRE1α in iNKT cells reduces cytokine production and protects mice from oxazolone colitis. We therefore propose that an IRE1α-dependent signaling cascade couples constitutive cytokine mRNA expression to the rapid induction of cytokine secretion and effector functions in activated iNKT cells.

PMID:
30559399
PMCID:
PMC6297233
DOI:
10.1038/s41467-018-07758-x
[Indexed for MEDLINE]
Free PMC Article

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