Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

  • Nat Cell Biol. 2017 Jun;19(6):698-710. doi: 10.1038/ncb3518.
Simon J Tavernier  1  2  3 ,  Fabiola Osorio  1  2  3 ,  Lana Vandersarren  1  2  3 ,  Jessica Vetters  1  2  3 ,  Nele Vanlangenakker  1  2  3 ,  Gert Van Isterdael  1  2  4 ,  Karl Vergote  1  2  3 ,  Riet De Rycke  4  5 ,  Eef Parthoens  4  5 ,  Lianne van de Laar  1  3  6 ,  Takao Iwawaki  7 ,  Juan R Del Valle  8 ,  Chih-Chi Andrew Hu  9 ,  Bart N Lambrecht  1  2  3  10 ,  Sophie Janssens  1  2  3
Affiliations
  • 1. Laboratory of Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, 9052 Ghent, Belgium.
  • 2. GROUP-ID Consortium, Ghent University and University Hospital, 9000 Ghent, Belgium.
  • 3. Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium.
  • 4. VIB Bioimaging Core, 9052 Ghent, Belgium.
  • 5. Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
  • 6. Department of Rheumatology &Clinical Immunology, Laboratory of Translational Immunology, Utrecht University Medical Center, 3584 Utrecht, The Netherlands.
  • 7. Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, 920-0856 Kanazawa, Japan.
  • 8. Department of Chemistry, University of South Florida, Tampa, Florida 33620, USA.
  • 9. Department of Translational Tumor Immunology, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
  • 10. Department of Pulmonary Medicine, ErasmusMC, 2040 Rotterdam, The Netherlands.
PMID: 28459443 DOI: 10.1038/ncb3518
Abstract

The IRE1-XBP1 signalling pathway is part of a cellular programme that protects against endoplasmic reticulum (ER) stress, but also controls development and survival of immune cells. Loss of XBP1 in splenic type 1 conventional dendritic cells (cDC1s) results in functional alterations without affecting cell survival. However, in mucosal cDC1s, loss of XBP1 impaired survival in a tissue-specific manner-while lung cDC1s die, intestinal cDC1s survive. This was not caused by differential activation of ER stress cell-death regulators CHOP or JNK. Rather, survival of intestinal cDC1s was associated with their ability to shut down protein synthesis through a protective integrated stress response and their marked increase in regulated IRE1-dependent messenger RNA decay. Furthermore, loss of IRE1 Endonuclease on top of XBP1 led to cDC1 loss in the intestine. Thus, mucosal DCs differentially mount ATF4- and IRE1-dependent adaptive mechanisms to survive in the face of ER stress.

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