Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions

Nat Cell Biol. 2020 Oct;22(10):1162-1169. doi: 10.1038/s41556-020-00581-x. Epub 2020 Sep 21.


Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life1-3. Little is known about the proteostasis mechanism that safeguards stem cells. Here we report endoplasmic reticulum-associated degradation (ERAD) as a protein quality checkpoint that controls the haematopoietic stem cell (HSC)-niche interaction and determines the fate of HSCs. The SEL1L-HRD1 complex, the most conserved branch of ERAD4, is highly expressed in HSCs. Deletion of Sel1l led to niche displacement of HSCs and a complete loss of HSC identity, and allowed highly efficient donor-HSC engraftment without irradiation. Mechanistic studies identified MPL, the master regulator of HSC identity5, as a bona fide ERAD substrate that became aggregated in the endoplasmic reticulum following ERAD deficiency. Restoration of MPL signalling with an agonist partially rescued the number and reconstitution capacity of Sel1l-deficient HSCs. Our study defines ERAD as an essential proteostasis mechanism to safeguard a healthy stem cell pool by regulating the stem cell-niche interaction.

Publication types

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

MeSH terms

  • Animals
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum-Associated Degradation*
  • Female
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Thrombopoietin / genetics
  • Receptors, Thrombopoietin / metabolism*
  • Stem Cell Niche*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Mpl protein, mouse
  • Receptors, Thrombopoietin
  • Sel1h protein, mouse
  • Syvn1 protein, mouse
  • Ubiquitin-Protein Ligases