Regulation of mitochondrial dynamics by ERAD

ERAD 调节线粒体动力学

基本信息

批准号：
9934815
负责人：
Ling Qi
金额：
$ 6.07万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

项目摘要

Regulation of Mitochondrial Dynamics by ERAD ABSTRACT Cells face a complex challenge of balancing protein folding and degradation in the endoplasmic reticulum (ER), a multifunctional organelle that is central to human health. Further, dysregulation of this balance accounts for the pathogenesis of many human diseases. ER-associated degradation (ERAD) is a principal quality-control mechanism used by the cells to target misfolded proteins in the ER for proteasomal degradation in the cytosol. However, the physiological function of distinct mammalian ERAD components remain largely unclear. In the last several years, we have explored the physiological importance of cell type-specific ERAD in normal physiology and disease, and have identified molecular substrates and pathways underpinning ERAD- associated pathophysiology. While ERAD expression is known to be controlled by IRE1a signaling of the UPR, we recently discovered a negative feedback loop in which the Sel1L-Hrd1 protein complex of mammalian ERAD restrains IRE1a signaling and activation under the steady state by targeting IRE1a for proteasomal degradation. This study demonstrates an intimate crosstalk between the two most conserved ER quality- control systems. Surprisingly, our recent data in brown adipocytes reveals that Sel1L-Hrd1 ERAD may regulate mitochondrial dynamics, in part via IRE1a. Sel1L-deficient brown adipocytes exhibit a profound morphological alteration of mitochondria in response to cold exposure, which can be partially rescued upon the deletion of IRE1a. One of the major goals for the next five years is to delineate the molecular mechanism underlying the regulation of mitochondrial dynamics by ERAD by testing the overarching hypothesis that Sel1L-Hrd1 ERAD regulates mitochondrial dynamics and function via IRE1a. We will explore whether and how the “Sel1L- Hrd1 ERAD-IRE1a” axis of ER quality control machineries exerts control over mitochondrial fission-fusion balance. This study may not only reveal the significance of an “ERAD-UPR” crosstalk at the core of normal cellular function and physiology, but may also provide exciting insights into the organelle crosstalk, a largely mysterious process. With funding support from NIGMS, we have made great progress towards the understanding of the ERAD- UPR biology in mammals in the past several years. Hence, we are uniquely positioned to lead this project with innovation, passion and dedication to scientific discovery. The R35 grant mechanism will give us the intellectual freedom, time and resources to direct our energy for exploration into discovery and will open up new directions to provide unprecedented insights into the role of ER quality-control machineries in mitochondrial biology.

ERAD 对线粒体动力学的调节抽象的细胞面临着平衡内质网 (ER) 中蛋白质折叠和降解的复杂挑战，此外，这种平衡的失调也是对人类健康至关重要的多功能细胞器。许多人类疾病的发病机制是 ER 相关降解 (ERAD) 的主要质量控制。细胞使用的机制来靶向内质网中错误折叠的蛋白质，以在胞质溶胶中进行蛋白酶体降解。然而，不同哺乳动物 ERAD 成分的生理功能仍不清楚。过去几年，我们探索了细胞类型特异性 ERAD 在正常情况下的生理重要性生理学和疾病，并确定了支持 ERAD- 的分子底物和途径虽然已知 ERAD 表达受 UPR 的 IRE1a 信号控制，我们最近发现了一个负反馈环路，其中哺乳动物的 Sel1L-Hrd1 蛋白复合物 ERAD 通过针对蛋白酶体的 IRE1a 抑制稳态下的 IRE1a 信号传导和激活这项研究证明了两种最保守的 ER 质量之间存在密切的串扰—— 令人惊讶的是，我们最近在棕色脂肪细胞中的数据表明 Sel1L-Hrd1 ERAD 可能会调节。 Sel1L 缺陷的棕色脂肪细胞部分通过线粒体动力学表现出深刻的形态学。线粒体因冷暴露而发生的改变，通过删除 IRE1a。未来五年的主要目标之一是描绘其背后的分子机制。通过测试 Sel1L-Hrd1 ERAD 的总体假设，ERAD 对线粒体动力学的调节我们将探讨“Sel1L-”是否以及如何调节线粒体动力学和功能。 Hrd1 ERAD-IRE1a” ER 质量控制机制轴对线粒体裂变融合进行控制这项研究可能不仅揭示了正常核心的“ERAD-UPR”串扰的重要性。细胞功能和生理学，但也可能为细胞器串扰提供令人兴奋的见解，这在很大程度上是神秘的过程。在 NIGMS 的资助下，我们在理解 ERAD- 因此，我们在过去几年中处于独特的地位来领导这个项目。 R35 资助机制将为我们提供创新、热情和奉献精神。知识自由、时间和资源，引导我们的精力探索发现，并将开放新方向为 ER 质量控制机制的作用提供前所未有的见解线粒体生物学。