Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions.,Nature Cell Biology

当前位置： X-MOL 学术 › Nat. Cell Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-09-21 , DOI: 10.1038/s41556-020-00581-x
Longyong Xu _{1,

2} , Xia Liu _{1,

2} , Fanglue Peng _{1,

2} , Weijie Zhang _{1,

2} , Liting Zheng ₃ , Yao Ding _{1,

2} , Tianpeng Gu _{1,

4} , Kaosheng Lv _{5,

6} , Jin Wang ₇ , Laura Ortinau ₈ , Tianyuan Hu ₈ , Xiangguo Shi ₈ , Guojun Shi ₉ , Ge Shang ₁ , Shengyi Sun ₁₀ , Takao Iwawaki ₁₁ , Yewei Ji ₉ , Wei Li _{1,

2} , Jeffrey M Rosen _{1,

2} , Xiang H-F Zhang _{1,

2} , Dongsu Park ₈ , Stanley Adoro ₁₂ , Andre Catic _{1,

2} , Wei Tong _{5,

6} , Ling Qi ₉ , Daisuke Nakada ₈ , Xi Chen _{1,

2}

Affiliation

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular and Integrative Physiology and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan.
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Stem cells need to be protected from genotoxic and proteotoxic stress to maintain a healthy pool throughout life^1,2,3. 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 ERAD⁴, 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 identity⁵, 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.

中文翻译：

通过内质网相关降解的蛋白质质量控制维持造血干细胞特性和生态位相互作用。

需要保护干细胞免受基因毒性和蛋白质毒性压力，以在整个生命中保持健康的池^1,2,3。关于保护干细胞的蛋白质稳态机制知之甚少。在这里，我们报告了内质网相关降解 (ERAD) 作为控制造血干细胞 (HSC)-生态位相互作用并决定 HSC 命运的蛋白质质量检查点。SEL1L-HRD1 复合物是 ERAD ⁴最保守的分支，在 HSC 中高度表达。Sel1l的删除导致 HSC 的生态位置换和 HSC 身份的完全丧失，并允许高效的供体-HSC 植入而无需辐照。机制研究确定了 MPL，HSC 身份^{5的主要调节器}，作为真正的 ERAD 底物，在 ERAD 缺乏后在内质网中聚集。用激动剂恢复 MPL 信号传导部分挽救了Sel1l 缺陷型HSC 的数量和重组能力。我们的研究将 ERAD 定义为一种重要的蛋白质稳态机制，通过调节干细胞-生态位相互作用来保护健康的干细胞库。

更新日期：2020-09-21

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11