Regulation of Mitochondrial Dynamics by ERAD: Administrative Supplement

ERAD对线粒体动力学的调控 摘要 细胞面临一个复杂的挑战，即平衡内质网(ER)中的蛋白质折叠和降解。 对人类健康至关重要的多功能细胞器。此外，这种平衡的失调解释了 许多人类疾病的发病机制。ER相关降解(ERAD)是主要的质量控制方法 细胞用来靶向内质网中错误折叠的蛋白质的机制，以降解胞浆中的蛋白酶体。 然而，哺乳动物ERAD的不同组成部分的生理功能在很大程度上仍不清楚。在 在过去的几年里，我们已经探索了细胞类型特异性ERAD在正常人群中的生理意义 生理和疾病，并确定了支持ERAD的分子底物和途径- 相关的病理生理学。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，哺乳动物的Sel1L-Hrd1蛋白复合体 ERAD通过靶向蛋白酶体抑制IRE1a信号转导和激活 退化。这项研究展示了两种最保守的ER质量之间的亲密串扰- 控制系统。令人惊讶的是，我们最近在棕色脂肪细胞中的数据显示，Sel1L-Hrd1 ERAD可能调节 线粒体动力学，部分通过IRE1a。Sel1L缺乏的棕色脂肪细胞表现出深刻的形态 线粒体对冷暴露的反应改变，这可以在缺失后部分挽救 IRE1a.未来五年的主要目标之一是描绘出 ERAD通过验证Sel1L-Hrd1 ERAD的主要假说来调节线粒体动力学 通过IRE1a调节线粒体的动力学和功能。我们将探讨是否以及如何使用“Sel1L- Hrd1 ERAD-IRE1a“内质网质控机”轴对线粒体裂变融合进行控制 平衡。这项研究可能不仅揭示了ERAD-UPR串扰在NORMAL的核心意义 细胞功能和生理学，但也可能提供对细胞器串扰的令人兴奋的见解，在很大程度上 神秘的过程。 在NIGMS的资助下，我们在理解ERAD方面取得了很大进展- 过去几年在哺乳动物中的UPR生物学研究。因此，我们在领导该项目方面具有得天独厚的优势 创新、热情和对科学发现的奉献精神。R35赠款机制将为我们提供 智力自由，时间和资源，引导我们的精力探索到发现，并将开放 为ER质量控制机制在以下方面的作用提供前所未有的见解 线粒体生物学。

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.