通过准TMED货物受体来挽救受损的乌罗摩杜林贩运
Silvana Bazua-Valenti1,2,3, Matthew R Brown1, Jason Zavras1
1The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
The Journal of clinical investigation
|December 16, 2024
概括
用小分子准TMED蛋白质可以改善脏疾病模型中的尿模素 (UMOD) 贩运. 这种方法减少了突变UMOD积累和脏损伤,为脏蛋白质病症提供了潜在的治疗方法.
科学领域:
- 腎臟病學 (nephrology) 是一種醫學專業.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 尿模素 (UMOD) 的贩运在病的发病过程中至关重要.
- 在UMOD基因的突变导致自体主导管间脏病 (ADTKD-UMOD),导致功能衰竭由于细胞内突变的UMOD陷.
- 破坏UMOD走私的确切机制尚未完全理解.
研究的目的:
- 调查跨膜Emp24蛋白传输域含 (TMED) 货物受体在UMOD贩运中的作用.
- 评估TMED向小分子作为ADTKD-UMOD和其他脏蛋白病的治疗策略.
主要方法:
- 确定了TMED2,TMED9和TMED10作为UMOD绑定的货物受体.
- 使用了细胞培养,患者衍生器官和突变的UMOD-knockin小鼠.
- 管理TMED向小分子以评估UMOD贩运和脏健康标志物.
主要成果:
- 发现TMED2,TMED9和TMED10可以结合UMOD并调节其分泌途径的流通.
- TMEDs的药理向在体外和体内减少了细胞内突变UMOD的积累.
- TMED抑制恢复了UMOD局部化到顶端血,并减轻了ER压力,损伤和纤维化标志物.
结论:
- TMED货物接收器是UMOD贩运的关键监管器.
- 针对TMED的小分子代表了ADTKD-UMOD和其他脏蛋白病的有希望的治疗途径.
- 这项研究阐明了一种新的治疗策略,用于遗传性脏疾病,涉及到蛋白质的非法贩运.
相关概念视频
01:32Export of Misfolded Proteins out of the ER
3.5K
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...
3.5K
01:15Receptor Downregulation in MVBs
2.0K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.0K
01:19Translocation of Proteins into the Mitochondria
3.0K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.0K
01:37The Unfolded Protein Response
4.4K
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...
4.4K
01:06Carrier-Mediated Transport
254
Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
254
01:45ER Retrieval Pathway
3.8K
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
3.8K