| First Author | Xu L | Year | 2020 |
| Journal | Nat Cell Biol | Volume | 22 |
| Issue | 10 | Pages | 1162-1169 |
| PubMed ID | 32958856 | Mgi Jnum | J:327126 |
| Mgi Id | MGI:6709609 | Doi | 10.1038/s41556-020-00581-x |
| Citation | Xu L, et al. (2020) Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions. Nat Cell Biol 22(10):1162-1169 |
| abstractText | Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life(1-3). 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 ERAD(4), 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 identity(5), 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. |
