γ-分泌酶促进了复原体介导的逆行运输
Yuka Takeo1, Mac Crite1,2, Daniel DiMaio1,3,4,5
1Department of Genetics, Yale School of Medicine.
bioRxiv : the preprint server for biology
|June 19, 2024
概括
逆转激素复合物促进逆向运输,但其功能因抑制或消除γ-分泌酶而受损. 这表明,g-分泌酶活性对于逆转激素介导的蛋白质贩运至关重要.
科学领域:
- 细胞生物学 细胞生物学
- 神经科学是一个神经科学.
- 分子生物学分子生物学
背景情况:
- 逆转激素复合体对于从内分体到跨戈尔吉网络 (TGN) 的逆向蛋白质运输至关重要.
- γ-分泌酶是一种蛋白酶复合体,涉及诸如阿尔茨海默氏症 (AD) 等神经退行性疾病.
- 以前的研究表明,逆转激素和γ-分泌酶之间存在相互作用,但其功能意义尚不清楚.
研究的目的:
- 为了研究逆转激素复合物和γ-分泌酶之间的相互作用的功能后果.
- 为了确定g-分泌酶活动是否会影响逆转激素介导的逆向贩运.
主要方法:
- 利用培养的人类上皮细胞.
- 使用特定抑制剂 (XXI) 抑制γ-分泌酶活性.
- 通过将其催化子单元 (PS1) 敲除,基因消除了γ-分泌酶.
- 评估了各种依赖逆流体和独立货物的贩运情况.
主要成果:
- 抑制或基因消除的g-分泌酶受损的内分体到TGN的逆转基因依赖的货物 (DMT1-II,CIMPR, shiga毒素) 的贩运.
- 反转激素独立货物的贩运不受g-分泌酶抑制的影响.
- γ-分泌酶抑制和PS1淘汰减少了γ-分泌酶和逆转激素之间的相互作用,但不是货物-逆转激素或货物-γ-分泌酶的相互作用.
- 这些治疗没有改变Rab7-GTP水平,这表明逆转激素-载荷结合没有受到直接影响.
结论:
- γ-分泌酶和逆转激素之间的相互作用促进了逆转激素介导的逆向贩运.
- γ-分泌酶活性是必要的,以有效地从内体到TGN运输特定的货物.
- 这一发现为与逆转激素和γ-分泌酶功能障碍相关的神经退行性疾病背后的分子机制提供了新的见解.
相关概念视频
Export of Misfolded Proteins out of the ER
3.6K
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...
3.6K
ER 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
Recycling Endosomes and Transcytosis
2.6K
The recycling endosome, also known as the endosomal recycling compartment (ERC), is a part of the slow-recycling process of the endocytic pathway. Molecules internalized through receptor-mediated endocytosis are either degraded in the lysosomes or are recycled to the plasma membrane through the fast- or slow-recycling route.
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...
2.6K
Overview of Secretory Vesicles
8.5K
Secretory vesicles, also known as dense core vesicles (DCVs), are membrane-bound vesicles that transport secretory proteins, such as hormones or neurotransmitters. Regulated secretory vesicles transport proteins from the trans-Golgi network to the exterior of the cell. Proteins present in regulated secretory vesicles are required to be rapidly exocytosed in large amounts upon a specific stimulus.
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
8.5K
Protein Translocation Machinery on the ER Membrane
4.6K
The translocon complex situated on the ER membrane is the main gateway for the protein secretory pathway. It facilitates the transport of nascent peptides into the ER lumen and their insertion into the ER membrane.
Sec61 protein conducting channel
In eukaryotes, the translocon complex comprises a core heterotrimeric translocator channel called the Sec61 complex. This channel includes three transmembrane proteins, Sec61α, Sec61β, and Sec61γ, and is the largest subunit of the...
Sec61 protein conducting channel
In eukaryotes, the translocon complex comprises a core heterotrimeric translocator channel called the Sec61 complex. This channel includes three transmembrane proteins, Sec61α, Sec61β, and Sec61γ, and is the largest subunit of the...
4.6K
Transport Across the Golgi
4.2K
While it is unclear how molecules move between adjacent Golgi cisternae, it is apparent that the molecules move from cis- cisterna, the entry face, to the trans- cisterna, the exit face. Experiments initially suggested vesicles that bud from one cisterna and fuse with the next cisterna to transport proteins between the cisternae. This vesicular transport model describes the Golgi apparatus as a relatively static structure with a unique enzyme composition in each cisterna. Molecules are...
4.2K


