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The role of ER associated degradation (ERAD) in hematopoietic stem cells

ER相关降解（ERAD）在造血干细胞中的作用

基本信息

批准号：
10649697
负责人：
Qing Li
金额：
$ 49.07万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649697
关键词：
ATF6 gene Area Binding Blood Blood Cells Cells Complex Cytosol Data Defect Dependence Dislocations Endoplasmic Reticulum Ensure Equilibrium FRAP1 gene Failure Genes Hematological Disease Hematopoietic Hematopoietic stem cells Knock-out Knockout Mice Malignant Neoplasms Mediating Metabolic Output PIK3CG gene PTEN gene Pathway interactions Play Production Proliferating Protein Biosynthesis Proteins Quality Control Regulation Reporting Research Role Signal Pathway Signal Transduction Sirolimus Stress System Transplant Recipients Ubiquitination XBP1 gene blood treatment cell regeneration conditional knockout endoplasmic reticulum stress exhaustion hematopoietic differentiation hematopoietic stem cell differentiation hematopoietic stem cell fate hematopoietic stem cell quiescence hematopoietic stem cell self-renewal hematopoietic tissue insight mTOR Signaling Pathway mTOR inhibition misfolded protein novel novel strategies preservation proteostasis reconstitution response self-renewal stem cell function stem cell proliferation ubiquitin-protein ligase

项目摘要

Abstract: It is well established that quiescence or dormancy preserves the self-renewal and long-term reconstituting potential of long-term HSCs (LT-HSC). HSCs that are quiescent give rise to much higher reconstitution than proliferating HSCs in transplant recipients, and signals that drive HSCs into proliferation cycle often lead to HSC differentiation and exhaustion. However, the mechanisms that coordinate HSC quiescence, proliferation and differentiation remains to be investigated. Recently, we and others reported that protein homeostasis at endoplasmic reticulum (ER) plays important role in preserving HSC functions under stressed condition. However, it remains to be investigated whether protein quality control is important for HSCs under steady state, when the majority of HSCs remain in a deeply dormant state with profoundly reduced protein synthesis rate and metabolic activity. ER associated degradation (ERAD) is a critical component of protein homeostasis, and ensures protein quality control by degrading inappropriately folded or assembled proteins in ER. ERAD complexes recognize misfolded proteins in ER and translocate them to cytosol for proteasomal degradation. Our preliminary studies indicate that protein quality control via ERAD governs HSC quiescence and self-renewal. 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 complete loss of HSC self-renewal and HSC depletion. ERAD deficiency via Sel1L knockout induces a non-apoptotic ER stress and activates all three main pathways of unfolded protein response (UPR). Furthermore, we found that mTOR signaling is activated in Sel1L knockout HSCs and inhibition of mTOR via rapamycin rescues Sel1L knockout-induced HSC defects. We therefore hypothesize that Sel1L maintains HSC quiescence and self-renewal by restricting mTORC activity. Here, we propose three aims to determine the mechanism by which ERAD modulates mTOR signaling to preserve HSC quiescence and self-renewal: 1) Determine the role of Akt/mTOR signaling branches in Sel1L-mediated HSC regulation; 2) Dissect the interaction of ERAD and UPR signaling; and 3) Determine the role of Rheb in ERAD deficiency-induced HSC dysregulation. These studies will establish Sel1L/Hrd1 ERAD as the master regulator of HSC quiescence, and provide novel insights into how protein quality control systems coordinate with proliferation signaling pathways to determine HSC fate.

摘要：众所周知，静止或休眠可以保持自我更新和长期重建。长期造血干细胞的潜能(LT-HSC)。静止的肝星状细胞所产生的重构远高于移植受者中HSC的增殖，以及促使HSC进入增殖周期的信号通常会导致HSC 分化和耗竭。然而，协调HSC静止、增殖和分化还有待研究。最近，我们和其他人报道了蛋白质动态平衡在内质网(ER)在应激状态下维持HSC功能方面起着重要作用。然而，蛋白质质量控制对稳定状态下的HSCs是否重要仍有待调查，当大多数肝星状细胞仍处于深度休眠状态，蛋白质合成率和代谢显著降低。活动。内质网相关降解(ERAD)是蛋白质动态平衡的重要组成部分，并确保蛋白质通过降解内质网中不适当折叠或组装的蛋白质进行质量控制。ERAD复合体识别在内质网中错误折叠的蛋白质，并将它们转移到胞浆中进行蛋白酶体降解。我们的初步研究提示通过ERAD的蛋白质质量控制调控HSC的静止和自我更新。Sel1L/Hrd1 ERAD 基因在静止和不活跃的HSCs中丰富，在造血系统中条件基因敲除Sel1L 组织促使HSC过度增殖，导致HSC自我更新完全丧失，HSC耗竭。通过Sel1L基因敲除的ERAD缺乏症诱导非凋亡性内质网应激并激活所有三条主要途径未折叠蛋白反应(UPR)。此外，我们还发现，在Sel1L基因敲除过程中，mTOR信号被激活 HSCs和通过雷帕霉素抑制mTOR可挽救Sel1L基因敲除诱导的HSC缺陷。因此，我们假设Sel1L通过限制mTORC活性来维持HSC的静止和自我更新。在这里，我们提出三个目标来确定ERAD调节mTOR信号以保护HSC的机制静止与自我更新：1)确定Akt/mTOR信号分支在Sel1L介导的HSC中的作用 2)分析ERAD和UPR信号的相互作用；3)确定Rheb在ERAD中的作用缺乏所致的HSC调节失调。这些研究将确立Sel1L/Hrd1 ERAD为主调节器，并为蛋白质质量控制系统如何与增殖信号通路决定了HSC的命运。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exploring the Molecular Landscape of Myelofibrosis, with a Focus on Ras and Mitogen-Activated Protein (MAP) Kinase Signaling.

DOI：
10.3390/cancers15184654
发表时间：
2023-09-21
期刊：
CANCERS
影响因子：
5.2
作者：
Reynolds, Samuel B.;Pettit, Kristen;Kandarpa, Malathi;Talpaz, Moshe;Li, Qing
通讯作者：
Li, Qing

Assessment of Cellular Bioenergetics in Mouse Hematopoietic Stem and Primitive Progenitor Cells using the Extracellular Flux Analyzer.

使用细胞外通量分析仪评估小鼠造血干细胞和原始祖细胞的细胞生物能学。