PT  - JOURNAL ARTICLE
AU  - Lu Liu
AU  - Ayaka Inoki
AU  - Kelly Fan
AU  - Fengbiao Mao
AU  - Guojun Shi
AU  - Xi Jin
AU  - Meiling Zhao
AU  - Gina Ney
AU  - Shengyi Sun
AU  - Yali Dou
AU  - Ken Inoki
AU  - Ling Qi
AU  - Qing Li
TI  - Endoplasmic reticulum associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity
AID  - 10.1101/709964
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 709964
4099  - http://biorxiv.org/content/early/2019/07/21/709964.short
4100  - http://biorxiv.org/content/early/2019/07/21/709964.full
AB  - Many tissue-specific stem cells require quiescence to sustain stem cell pool and maintain lifelong tissue integrity. It remains unclear whether protein quality control is required for stem cells in quiescence when RNA content, protein synthesis and metabolic activities are significantly reduced. Here, we report that endoplasmic reticulum associated degradation (ERAD) is required to preserve the function of quiescent hematopoietic stem cells (HSC). The Sel1L/Hrd1 ERAD genes are enriched in the quiescent and inactive HSCs, and conditional knockout of Sel1L in hematopoietic tissues drives HSCs to hyper-proliferation which leads to reduced self-renewal and HSC depletion. ERAD deficiency induces a non-apoptotic ER stress and activates unfolded protein response (UPR). Furthermore, Sel1L knockout leads to mTOR activation, and mTOR inhibition rescues the HSC defects in Sel1L knockout mice. Protein quality control is, therefore, tightly regulated and actively engaged in quiescent HSCs. Sel1L/Hrd1 ERAD maintains HSC quiescence and self-renewal via restricting mTOR activity.