Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells

Nat Cell Biol. 2019 Mar;21(3):328-337. doi: 10.1038/s41556-019-0285-6. Epub 2019 Feb 18.

Abstract

Over their lifetime, long-term haematopoietic stem cells (HSC) are exposed to a variety of stress conditions that they must endure. Many stresses, such as infection/inflammation, reactive oxygen species, nutritional deprivation and hypoxia, activate unfolded protein response signalling, which induces either adaptive changes to resolve the stress or apoptosis to clear the damaged cell. Whether unfolded-protein-response signalling plays any role in HSC regulation remains to be established. Here, we report that the adaptive signalling of the unfolded protein response, IRE1α-XBP1, protects HSCs from endoplasmic reticulum stress-induced apoptosis. IRE1α knockout leads to reduced reconstitution of HSCs. Furthermore, we show that oncogenic N-RasG12D activates IRE1α-XBP1, through MEK-GSK3β, to promote HSC survival under endoplasmic reticulum stress. Inhibiting IRE1α-XBP1 abolished N-RasG12D-mediated survival under endoplasmic reticulum stress and diminished the competitive advantage of NrasG12D HSCs in transplant recipients. Our studies illuminate how the adaptive endoplasmic reticulum stress response is advantageous in sustaining self-renewal of HSCs and promoting pre-leukaemic clonal dominance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Cell Self Renewal / genetics*
  • Cell Survival / genetics
  • Endoplasmic Reticulum Stress / genetics*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Hematopoietic Stem Cells / metabolism*
  • Leukemia / genetics
  • Leukemia / metabolism
  • Leukemia / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Precancerous Conditions
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / genetics
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism*

Substances

  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Monomeric GTP-Binding Proteins
  • Nras protein, mouse