PMID- 33150381
OWN - NLM
STAT- MEDLINE
DCOM- 20210405
LR  - 20230621
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 136
IP  - 26
DP  - 2020 Dec 24
TI  - ER-associated degradation preserves hematopoietic stem cell quiescence and 
      self-renewal by restricting mTOR activity.
PG  - 2975-2986
LID - 10.1182/blood.2020007975 [doi]
AB  - Hematopoietic stem cells (HSC) self-renew to sustain stem cell pools and 
      differentiate to generate all types of blood cells. HSCs remain in quiescence to 
      sustain their long-term self-renewal potential. It remains unclear whether 
      protein quality control is required for stem cells in quiescence when RNA 
      content, protein synthesis, and metabolic activities are profoundly reduced. 
      Here, we report that protein quality control via endoplasmic reticulum-associated 
      degradation (ERAD) governs the function of quiescent HSCs. The Sel1L/Hrd1 ERAD 
      genes are enriched in the quiescent and inactive HSCs, and conditional knockout 
      of Sel1L in hematopoietic tissues drives HSCs to hyperproliferation, which leads 
      to complete loss of HSC self-renewal and HSC depletion. Mechanistically, ERAD 
      deficiency via Sel1L knockout leads to activation of mammalian target of 
      rapamycin (mTOR) signaling. Furthermore, we identify Ras homolog enriched in 
      brain (Rheb), an activator of mTOR, as a novel protein substrate of Sel1L/Hrd1 
      ERAD, which accumulates upon Sel1L deletion and HSC activation. Importantly, 
      inhibition of mTOR, or Rheb, rescues HSC defects in Sel1L knockout mice. Protein 
      quality control via ERAD is, therefore, a critical checkpoint that governs HSC 
      quiescence and self-renewal by Rheb-mediated restriction of mTOR activity.
CI  - (c) 2020 by The American Society of Hematology.
FAU - Liu, Lu
AU  - Liu L
AD  - Department of Internal Medicine.
FAU - Inoki, Ayaka
AU  - Inoki A
AD  - Department of Internal Medicine.
FAU - Fan, Kelly
AU  - Fan K
AD  - Department of Internal Medicine.
FAU - Mao, Fengbiao
AU  - Mao F
AD  - Department of Pathology.
FAU - Shi, Guojun
AU  - Shi G
AD  - Department of Molecular & Integrative Physiology, and.
FAU - Jin, Xi
AU  - Jin X
AD  - Department of Internal Medicine.
FAU - Zhao, Meiling
AU  - Zhao M
AD  - Department of Internal Medicine.
FAU - Ney, Gina
AU  - Ney G
AD  - Department of Pediatrics, University of Michigan, Ann Arbor, MI.
FAU - Jones, Morgan
AU  - Jones M
AD  - Department of Internal Medicine.
FAU - Sun, Shengyi
AU  - Sun S
AD  - Center for Molecular Medicine and Genetics, Department of Microbiology, 
      Immunology, and Biochemistry, Wayne State University School of Medicine, Detroit, 
      MI; and.
FAU - Dou, Yali
AU  - Dou Y
AD  - Department of Pathology.
FAU - Inoki, Ken
AU  - Inoki K
AD  - Department of Internal Medicine.
AD  - Department of Molecular & Integrative Physiology, and.
FAU - Qi, Ling
AU  - Qi L
AD  - Department of Internal Medicine.
AD  - Department of Molecular & Integrative Physiology, and.
FAU - Li, Qing
AU  - Li Q
AD  - Department of Internal Medicine.
AD  - Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, 
      MI.
LA  - eng
GR  - T32 HL007622/HL/NHLBI NIH HHS/United States
GR  - R01 HL150707/HL/NHLBI NIH HHS/United States
GR  - R01 HL132392/HL/NHLBI NIH HHS/United States
GR  - R01 CA232263/CA/NCI NIH HHS/United States
GR  - T32 CA009357/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 0 (Rheb protein, mouse)
RN  - 0 (Sel1h protein, mouse)
RN  - EC 2.3.2.27 (Syvn1 protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Blood. 2020 Dec 24;136(26):2967-2968. PMID: 33367552
MH  - Animals
MH  - *Cell Proliferation
MH  - Endoplasmic Reticulum/genetics/*metabolism
MH  - *Endoplasmic Reticulum-Associated Degradation
MH  - Hematopoietic Stem Cells/*metabolism
MH  - Intracellular Signaling Peptides and Proteins/genetics/metabolism
MH  - Mice
MH  - Ras Homolog Enriched in Brain Protein/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
PMC - PMC7770563
COIS- Conflict-of-interest disclosure: The authors declare no competing financial 
      interests.
EDAT- 2020/11/06 06:00
MHDA- 2021/04/07 06:00
PMCR- 2021/12/24
CRDT- 2020/11/05 06:09
PHST- 2020/07/01 00:00 [received]
PHST- 2020/10/09 00:00 [accepted]
PHST- 2020/11/06 06:00 [pubmed]
PHST- 2021/04/07 06:00 [medline]
PHST- 2020/11/05 06:09 [entrez]
PHST- 2021/12/24 00:00 [pmc-release]
AID - S0006-4971(20)83894-4 [pii]
AID - 2020/BLD2020007975 [pii]
AID - 10.1182/blood.2020007975 [doi]
PST - ppublish
SO  - Blood. 2020 Dec 24;136(26):2975-2986. doi: 10.1182/blood.2020007975.