Defining the Central Role of ER-Associated Degradation (ERAD) in Neuroendocrine Cells

定义 ER 相关降解 (ERAD) 在神经内分泌细胞中的核心作用

基本信息

批准号：
10219237
负责人：
Ling Qi
金额：
$ 40.51万
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：
2018
资助国家：
美国
起止时间：
2018-09-22 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219237
关键词：
Autophagocytosis Behavior Biological Models Biology Cell Death Cell physiology Cells Clinical Defect Diabetes Insipidus Disease Eating Endoplasmic Reticulum Energy Metabolism Ensure Environment Equilibrium Exhibits Failure Health Homeostasis Human Impairment In Vitro Investigation Laboratories Light Link Mediating Metabolic Diseases Modeling Molecular Molecular Conformation Molecular Weight Mus Neuroendocrine Cell Neurons Neuropeptides Pathogenesis Pathologic Physiological Physiology Play Prader-Willi Syndrome Process Production Protein Precursors Proteins Quality Control Rare Diseases Regulation Reporting Role System Testing The Sun Therapeutic Water cell type early-onset obesity human disease in vivo insight interest misfolded protein mutant prevent prohormone protein aggregation protein complex protein degradation protein folding recruit response restraint sensor targeted treatment

项目摘要

Defining the Central Role of ER-Associated Degradation (ERAD) in Neuroendocrine Cells SUMMARY My laboratory has a long-standing interest in protein folding and degradation within the endoplasmic reticulum (ER) by defining the physiological and pathological importance of mammalian ER quality-control machineries in vivo. ER-associated degradation (ERAD) is the principal protein quality-control mechanism responsible for targeting misfolded proteins in the ER for cytosolic proteasomal degradation. Failure to clear misfolded proteins in the ER presumably activates the unfolded protein response, or UPR. We showed that Sel1L-Hrd1 ERAD modulates the activation of UPR sensor IRE1a by mediating its turnover (Sun et al. 2015 Nat Cell Biol). In two recent studies, we reported that impaired ERAD function may be directly linked to the pathogenesis of metabolic diseases, thereby holding significant therapeutic potential (Shi et al. 2017 and Kim et al. 2018 J CIin Invest). Specifically, we reported that mice with Sel1L deficiency in either AVP or POMC neurons exhibit diabetes insipidus and early-onset obesity, respectively. We showed that Sel1L-Hrd1 ERAD controls the maturation of two prohormones, proAVP and POMC, within the ER by targeting the misfolded forms for proteasomal degradation, thereby preventing the aggregation of a large proportion of native prohormones. We now propose to test the overarching hypothesis that the Sel1L-Hrd1 ERAD protein complex plays a critical role in neuroendocrine cells by directly recruiting misfolded prohormones for proteasomal degradation and by coordinating the activation of other ER quality-control machineries, such as UPR and autophagy, to ensure proper prohormone maturation and neuronal homeostasis. This model challenges the current paradigm in ER biology by placing ERAD at the center of cellular function in normal physiology and disease pathogenesis. Using POMC neurons as a model system, we will accomplish the following Aims: (1) determine the underlying molecular mechanisms and therapeutic potential of ERAD-POMC interactions; (2) demonstrate the pathophysiological importance and mechanisms underlying the crosstalk between ERAD and autophagy in POMC neurons; and (3) demonstrate the pathophysiological importance and mechanisms underlying the crosstalk between ERAD and IRE1α in POMC neurons. This study will provide unprecedented insights into ERAD function and prohormone biology in neuroendocrine cells, which has direct clinical implications for human diseases that are associated with defects of prohormone folding and export. RELEVANCE TO HUMAN HEALTH: All neuropeptides are synthesized as precursor proteins known as “prohormones” in the ER; however, molecular mechanisms underlying their maturation within the ER remain poorly understood. This study will establish the pathophysiological significance of ERAD in coordinating ER homeostasis during prohormone maturation and explore the therapeutic potential of targeting ERAD in the treatment of diseases attributed to defects in prohormone maturation, such as diabetes insipidus, early-onset obesity, and other rare diseases such as Prader-Willi Syndrome.

定义 ER 相关降解 (ERAD) 在神经内分泌细胞中的核心作用概括我的实验室长期以来对内质网内的蛋白质折叠和降解感兴趣（ER）通过定义哺乳动物 ER 质量控制机制的生理和病理重要性 ER 相关降解 (ERAD) 是负责蛋白质质量控制的主要机制。针对内质网中错误折叠的蛋白质进行胞质蛋白酶体降解未能清除错误折叠的蛋白质。我们发现 Sel1L-Hrd1 ERAD 可能会激活未折叠蛋白反应（UPR）。通过介导 UPR 传感器 IRE1a 的更新来调节其激活（Sun 等人，2015 Nat Cell Biol）。最近的研究表明，ERAD 功能受损可能与代谢的发病机制直接相关疾病，从而具有显着的治疗潜力（Shi et al. 2017 and Kim et al. 2018 J CIin Invest）。具体来说，我们报道了 AVP 或 POMC 神经元中 Sel1L 缺陷的小鼠表现出糖尿病我们发现 Sel1L-Hrd1 ERAD 分别控制尿崩症和早发性肥胖的成熟。通过靶向蛋白酶体的错误折叠形式，在 ER 内产生两种激素原，proAVP 和 POMC 降解，从而防止大部分天然激素原的聚集。检验 Sel1L-Hrd1 ERAD 蛋白复合物在通过直接募集错误折叠的激素原进行蛋白酶体降解以及通过协调其他 ER 质量控制机制的激活，例如 UPR 和自噬，以确保该模型挑战了当前的 ER 范式。通过将 ERAD 置于正常生理学和疾病发病机制中细胞功能的中心来研究生物学。以 POMC 神经元作为模型系统，我们将完成以下目标：（1）确定底层 ERAD-POMC 相互作用的分子机制和治疗潜力；(2) 证明 ERAD 和自噬之间的相互作用的病理生理学重要性和机制 POMC 神经元；(3) 证明其病理生理学重要性和机制 POMC 神经元中 ERAD 和 IRE1α 之间的串扰这项研究将为我们提供前所未有的见解。神经内分泌细胞中的 ERAD 功能和激素原生物学，对人类具有直接的临床意义与激素原折叠和输出缺陷相关的疾病。与人类健康的相关性：所有神经肽都是作为前体蛋白合成的，称为然而，内质网中的“激素原”仍然存在，其成熟的分子机制仍然存在。这项研究将确定 ERAD 在协调 ER 中的病理生理学意义。激素原成熟过程中的稳态并探索靶向 ERAD 的治疗潜力治疗由激素原成熟缺陷引起的疾病，例如尿崩症、早发性糖尿病肥胖症和其他罕见疾病，例如普瑞德威利综合症。