Open AccessProtein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions
Author(s) -
Longyong Xu,
Xia Liu,
Fanglue Peng,
Weijie Zhang,
Liting Zheng,
Yao Ding,
Tianpeng Gu,
Kaosheng Lv,
Jin Wang,
Laura Ortinau,
Tianyuan Hu,
Xiangguo Shi,
Guojun Shi,
Guanning Shang,
Shengyi Sun,
Takao Iwawaki,
Yewei Ji,
Wei Li,
Jeffrey M. Rosen,
Xiang H.-F. Zhang,
Dongsu Park,
Stanley Adoro,
André Catic,
Wei Tong,
Ling Qi,
Daisuke Nakada,
Xi Chen
Publication year - 2020
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-020-00581-x
Subject(s) - endoplasmic reticulum , microbiology and biotechnology , haematopoiesis , niche , stem cell , biology , cell , biochemistry
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.