scholarly journals Endoplasmic reticulum associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity

2019 ◽  
Author(s):  
Lu Liu ◽  
Ayaka Inoki ◽  
Kelly Fan ◽  
Fengbiao Mao ◽  
Guojun Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Stem Cell ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Mtor Activity

SummaryMany 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.

scholarly journals ER-associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity

Blood ◽  
2020 ◽  
Vol 136 (26) ◽  
pp. 2975-2986 ◽  
Author(s):  
Lu Liu ◽  
Ayaka Inoki ◽  
Kelly Fan ◽  
Fengbiao Mao ◽  
Guojun Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Quality Control ◽  
Stem Cell ◽  
Protein Quality ◽  
Mammalian Target Of Rapamycin ◽  
Protein Quality Control ◽  
Conditional Knockout ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Mtor Activity

Abstract 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.

scholarly journals Hematopoietic Stem Cells Require Elevated Protein Quality Control

2018 ◽  
Vol 64 ◽  
pp. S104
Author(s):  
Robert Signer ◽  
Christopher Dillingham ◽  
Mary Jean Sunshine ◽  
Lorena Hidalgo San Jose ◽  
Miriama Kruta ◽  
...  
Keyword(s):  
Stem Cells ◽  
Quality Control ◽  
Hematopoietic Stem Cells ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Hematopoietic Stem ◽  
Elevated Protein

scholarly journals Lys11- and Lys48-linked ubiquitin chains interact with p97 during endoplasmic-reticulum-associated degradation

2014 ◽  
Vol 459 (1) ◽  
pp. 205-216 ◽  
Author(s):  
Matthew Locke ◽  
Julia I. Toth ◽  
Matthew D. Petroski
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Endoplasmic Reticulum Membrane ◽  
Endoplasmic Reticulum Associated Degradation

This study provides evidence that p97 interacts with proteins modified with Lys11- and Lys48-linked ubiquitin chains at the endoplasmic reticulum membrane, suggesting roles for these signals in protein quality control.

scholarly journals Protein quality control of cell stemness

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Pengze Yan ◽  
Jie Ren ◽  
Weiqi Zhang ◽  
Jing Qu ◽  
Guang-Hui Liu
Keyword(s):  
Stem Cells ◽  
Quality Control ◽  
Stem Cell ◽  
Protein Quality ◽  
Cell Function ◽  
Current Knowledge ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
High Rate ◽  
Potential Applications

AbstractProtein quality control (PQC) systems play essential roles in the recognition, refolding and clearance of aberrant proteins, thus ensuring cellular protein homeostasis, or proteostasis. Especially, continued proliferation and differentiation of stem cells require a high rate of translation; therefore, accurate PQC systems are essential to maintain stem cell function. Growing evidence suggested crucial roles of PQC systems in regulating the stemness and differentiation of stem cells. This review focuses on current knowledge regarding the components of the proteostasis network in stem cells, and the importance of proteostasis in maintaining stem cell identity and regenerative functions. A complete understanding of this process might uncover potential applications in aging intervention and aging-related diseases.

scholarly journals Endoplasmic Reticulum-Mediated Protein Quality Control and Endoplasmic Reticulum-Associated Degradation Pathway Explain the Reduction of N-glycoprotein Level Under the Lead Stress

2021 ◽  
Vol 11 ◽  
Author(s):  
Hong Du ◽  
Canqi Zheng ◽  
Muhmmad Aslam ◽  
Xihui Xie ◽  
Wanna Wang ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Level ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Misfolded Proteins ◽  
Pb Stress ◽  
Endoplasmic Reticulum Associated Degradation ◽  
High Lead ◽  
Erad Pathway

Different anthropogenic activities result in the continuous increase of metal lead (Pb) in the environment and adversely affect living organisms. Therefore, it is important to investigate the tolerance mechanism in a model organism. Chlamydomonas reinhardtii is an important green eukaryotic model microalga for studying different kinds of biological questions. In this study, the responses of C. reinhardtii were revealed via a comprehensive approach, including physiological, genomic, transcriptomic, glycomic, and bioinformatic techniques. Physiological results showed that the growth rate and soluble protein content were significantly reduced under the high lead stress. Also, the results obtained from the genomic and transcriptomic analyses presented that the endoplasmic reticulum-mediated protein quality control (ERQC) system and endoplasmic reticulum-associated degradation (ERAD) pathway were activated under the third day of high lead stress. The unique upregulated protein disulfide isomerase genes on the ERQC system were proposed to be important for the protein level and protein quality control. The accumulation of specific N-glycans indicated that specific N-glycosylation of proteins might alter the biological functions of proteins to alleviate the Pb stress in alga and/or lead to the degradation of incomplete/misfolded proteins. At the same time, it was observed that genes involved in each process of ERAD were upregulated, suggesting that the ERAD pathway was activated to assist the degradation of incomplete/misfolded proteins. Therefore, it is reasonable to speculate that the reduction of protein level under the high lead stress was related to the activated ERQC system and QRAD pathway. Our findings will provide a solid and reliable foundation and a proposed ERAD working model for further in-depth study of the ERQC system and ERAD pathway under the Pb stress and even other biotic and abiotic stresses.

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