A recent study published in Nature Cell Biology uncovers a novel mechanism underlying haematopoietic stem cell health. CADA members, Dr. Xi Chen at Baylor College of Medicine and Dr. Ling Qi at University of Michigan Medical School together reported that ERAD protein quality control machinery safeguards haematopoietic stem cell identity and niche location by ensuring the surface expression of MPL. Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life1,2,3. 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 signaling with an agonist partially rescued the number and reconstitution capacity of Sel1l-deficient HSCs. This study defines ERAD as an essential proteostasis mechanism to safeguard a healthy stem cell pool by regulating the stem cell–niche interaction.
