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 the stem cells. Here, we report Endoplasmic Reticulum-Associated Degradation (ERAD) as a protein quality checkpoint that controls hematopoietic stem cell (HSC)-niche interaction and determines the fate of HSC. SEL1L-HRD1 complex, the most conserved branch of ERAD4, is highly expressed in HSC. Deletion of Sel1l led to niche displacement of HSC, 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 ER upon ERAD deficiency. Restoration of MPL signaling 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 through regulating the stem cell-niche interaction.
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