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. Epub 2017 May 1.

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.

Publication types

  • Comparative Study

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Apoptosis
  • Cell Survival
  • Dendritic Cells / enzymology*
  • Dendritic Cells / pathology
  • Endoplasmic Reticulum Stress
  • Genotype
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / pathology
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Transgenic
  • Phenotype
  • Protein Biosynthesis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Respiratory Mucosa / enzymology*
  • Respiratory Mucosa / pathology
  • Signal Transduction
  • Time Factors
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Unfolded Protein Response
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism

Substances

  • Atf4 protein, mouse
  • Ddit3 protein, mouse
  • Membrane Proteins
  • RNA, Messenger
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • Ern2 protein, mouse
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases