细胞内膜网膜应激和未折叠的蛋白质反应:骨肌肉缩中的作用
Yanan Ji1, Quan Jiang2, Bingqian Chen3
1Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province 226001, PR China.
Biochemical pharmacology
|February 14, 2025
概括
细胞内膜网膜应激 (ERS) 和未折叠的蛋白质反应 (UPR) 是骨肌肉缩的关键分子机制. 了解这些途径为肌肉消耗疾病提供了新的治疗点.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生理学 生理学 生理学
背景情况:
- 骨肌肉缩是一种与许多疾病相关的普遍疾病,给社会和患者带来了重大负担.
- 关键的分子机制包括改变的蛋白质循环,炎症,氧化应激和器官功能障碍.
- 细胞内膜网膜应激 (ERS) 和未折叠的蛋白质反应 (UPR) 与肌肉缩有关,但尚未完全理解.
研究的目的:
- 阐明骨肌肉缩中ERS和UPR的分子机制.
- 讨论ERS和UPR对各种类型的肌肉缩的影响.
- 探索针对ERS和UPR的预防和治疗策略.
主要方法:
- 文献综述和综合现有关于ERS,UPR和骨肌肉缩的研究.
- 分析涉及肌肉消耗的分子途径.
- 检查针对ER压力的治疗干预措施.
主要成果:
- ERS和UPR是复杂的过程,通过各种分子事件导致骨肌肉缩.
- 这些途径与肌肉缩有关,这些途径与不使用,缓解衰竭,CKD,DM,ALS,SMA,SBMA,衰老,肉,肥胖和饥饿有关.
- 针对ERS和UPR的抑制剂和药物疗法显示出预防和治疗肌肉缩的潜力.
结论:
- 细胞内膜网膜 (ER) 在维持骨肌肉平衡方面发挥着至关重要的作用.
- 对ERS和UPR机制的更深入的理解为开发有效的骨肌肉缩治疗方法提供了新的见解.
- 准ERS和UPR通路为肌肉消耗条件提供了有前途的治疗途径.
相关概念视频
01:37The Unfolded Protein Response
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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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01:31Regulation of the Unfolded Protein Response
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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01:17Role of ER in the Secretory Pathway
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Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
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01:32Export of Misfolded Proteins out of the ER
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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01:26Protein Modifications in the RER
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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
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01:29Protein Folding Quality Check in the RER
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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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