ユビキチネーションは,ER-ファギーとエンドプラズマ網膜の改造を調節する

Alexis González¹, Adriana Covarrubias-Pinto¹, Ramachandra M Bhaskara^1,2,3

¹Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany.

Nature

|May 24, 2023

まとめ

ER-ファギー受容体FAM134Bのユビキチネーションは,そのクラスタリングを駆動し,エンドプラズマ網膜 (ER) の改造を促進する. このプロセスは細胞の需要とER-phagyの調節に不可欠です.

科学分野:

細胞生物学
分子生物学
オートファギーの研究

背景:

エンドプラズマ網膜 (ER) の改造は不可欠であり,ER-phagyによって起こります.
ER-phagy受容体はこのプロセスを媒介するが,その調節はよくわかっていない.

研究の目的:

ER-ファギー受容体の調節メカニズムを解明する.
FAM134B機能とER再構成におけるユビキチネーションの役割を調査する.

主な方法:

FAM134Bのユビキチネーションの分子動力学 (MD) シミュレーション
リポソームとユビキチン化FAM134Bを用いた膜再構成.
超高解像度顕微鏡と細胞内の定量画像分析

主要な成果:

FAM134Bのレチクロンホモロジー領域 (RHD) のユビキチネーションは,受容体クラスタリングとLC3B結合を促進する.
Ubiquitinationは,RHDの膜の曲線を誘導する能力を高め,大規模な脂質二層の再構築を促進します.
FAM134Bは,細胞内のユビキチン依存のナノクラスターとマイクロクラスターを形成し,オリゴメリゼーションとクラスターサイズを増やす.
E3リガゼAMFRは,受容体群の中で,FAM134Bのユビキチン化を触媒化し,ER-ファギーのダイナミクスを調節する.

結論:

ユービキチネーションは,ER-ファギー受容体の機能を制御し,ERの改造を促進します.
FAM134Bのクラスタリングは,ユビキチネーションによって媒介され,効率的なER-phagyにとって不可欠である.
このメカニズムにより,細胞は需要に基づいてER構造を制御できます.

さらに関連する動画

09:05

Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae

Published on: April 18, 2016

29.1K

06:06

In Vitro Analysis of E3 Ubiquitin Ligase Function

Published on: May 14, 2021

5.3K

関連する概念動画

01:32

Export of Misfolded Proteins out of the ER

3.7K

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...

3.7K

01:37

The Unfolded Protein Response

4.8K

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...

4.8K

01:31

Regulation of the Unfolded Protein Response

2.5K

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...

2.5K

02:58

Regulated Protein Degradation

7.4K

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...

7.4K

01:15

Receptor Downregulation in MVBs

2.1K

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...

2.1K

01:45

ER Retrieval Pathway

3.9K

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...