Core mechanism for enzyme damage repair

Written article | Stairs

##, As an important hydrolysis system in animal cells, is essential for timely removal of damaged protein and cellular device. More and more evidence shows that lymphatic damage has participated in aging and disease. Many animal models that delay aging show stronger lymphatic activity. Therefore, maintaining the integrity and hydrolysis ability of the lymphatic body can help delay aging and delay the occurrence of older diseases. However, although the hazards of lysomal damage have been discovered as early as 60 years ago, it was not until recent years that researchers have begun to explore the ways of animal cell monitoring and repairing lyssene damage.

On September 7, 2022, Jay xiaojun Tan (Tan Xiaojun) and the director of the Institute of Agenity of the Department of Cell Biology at the University of Pittsburgh and Toren Finkel co -published in the Nature magazine entitled A Phosphoinositide Signaling Pathway Mediates Rapid Lysosomal Repair. In this article, the author found a new PI4P lipid signal pathway inspired by lyssene damage by the analysis of the surface protein group of the lymphatic surgery before and after the damage, and determined that this new path was in the repair of the lymphatic restoration. The leading core role, clarifying the molecular mechanism of the PI4P signal to promote the intraviole-damaged iconic and lipid exchange, reveals the cholesterol and phospholipidine (PS PS transferred from the internal quality network to the lysomin (PS ) The important role in the restoration of the lyon, and proves that the downstream lipid -proof protein ATG2 finally directly repair the lyssene membrane with lipid transportation with the help of PS (Figure 1). The author named the new enzyme repair mechanism to PITT (Phosphoinositide-Initiated Membrane Tethering and Lipidtransport), and was the same name as Pitt of the University of Pittsburgh.

Figure 1. The PITT pathway is the core mechanism of the medium lysome of the lybranete

Although it is generally believed that damaged lysome can be degraded by autophagy or is quickly repaired by the ESCRT complex, but the lysome in the cells that lack ESCRT or spontaneous genes are still quickly repaired, indicating that there are additional repair ways in the cells Essence In order to find such a way, the author designed a protein group method to identify the protein that raised the enzyme. They position a biomantic enzyme Turboid on the surface of the lympicine to quickly mark and purify the surface protein of the lysomin (Figure 2). Through mass spectrometry comparison analysis, the author found that multiple proteins related to PI4P lipid signals are rich on the surface of the enzyme. These include the production of PI4P kinase PI4K2A, and the effect protein (ORP9/10/11/OSBP) of multiple PI4P, indicating that the surface of the enzyme can stimulate the new PI4P signal pathway.

Figure 2. Bioin marks and purification strategies of lymphatic surface protein

After multiple verifications, the author found that the surface of the enzymes did produce a large number of PI4P lipid signals (Figure 3), and these signals came completely from the specific recruitment of lipidase PI4K2A. Tap PI4K2A can completely block this new PI4P pathway. The author further confirmed that the PI4P directly promoted the recruitment of the ORP family effect protein. These ORP proteins were combined with the PI4P on the lyon and the other end. Instead. The occurrence of blocking the PI4P signal on the lymphatic body can completely inhibit the recruitment of the ORP family and the interaction between the internal quality network-lysome. However, if you want to block the interaction of the intraviole mesh and iconic in the PI4P signal, you need to knock out four ORP family proteins at the same time (ORP-QKO).

Figure 3. A large number of PI4P lipid signals appeared on the surface of the enzyme

At the internal network-lysome interaction point, ORP protein also mediates the lipid exchange between the intravascular mesh and the lysomy, and then converts the PI4P on the lympicine to cholesterol and PS (Figure 4). Cholesterol can significantly improve the stability and strength of the cell membrane. However, without cholesterol, the enrichment of PS on the lymphatic body can also greatly promote the repair of the lymphatic body. Researchers believe that PS's transfer itself is not enough to repair the enzyme vulnerabilities, because while transsing a PS molecule to the lyon, a PI4P molecule will be lost on the lymphatic body. Therefore, the enrichment of PS does not increase the number of lipids on the lymphatic body. The author infer that PS may activate other large -scale lipid transport proteins to fill the enzyme vulnerabilities.

Figure 4. Lipid exchange between ORP Family protein media and damaged iconic iconic

After further screening, the researchers found that lipid transport protein ATG2 can be activated by PS on the lyon, which plays a key role in the restoration of the lymphatic body. ATG2 recruitment can be quickly detected on the surface of the enzyme. In the cells knocked by ATG2, the restoration of the lymphatic body cannot be completed. ATG2 is like a tunnel connecting two cells, and a large amount of liposuction is transported to the enzyme repair vulnerability through its hydrophobic tunnel. It is worth mentioning that the functions of ATG2 in the repair and autophagy of ATG2 depend on their lipid transportation capacity, but these two functions are completely independent and interfered with each other. The author realizes one function of selectively blocking ATG2 in autophait or lysomytopenia repair through a series of means, not affecting another. Figure 5. The lack of PITT pathway exacerbates the diffusion of TAU fiber

The author found that the PITT pathway is the main and necessary ways to quickly repair the oscope. The PITT pathway can be activated by a multi -disease -related lymphatic damage, indicating that it is a universal lymphatic mass control mechanism. For example, the lack of PITT pathway will exacerbate the diffusion of TAU fiber (Figure 5), which is the key step in the progress of Alzheimer's disease. Lack of PITT pathway will also increase the accumulation of lipofuscin in cells; lipid brown is the pathological characteristics of aging lysome and is also known as aging symbol. Among the mouse models and human patients, the first key enzyme PI4K2A that lacks PITT pathways can cause severe neurodegeneration and premature premature aging. Before this study, the molecular foundation of these lesions was unclear. Therefore, the discovery of the PITT pathway is an important step in understanding and the treatment of aging and disease -related disorders. In the future research work, the author plans to find small molecular drugs that can stimulate PITT pathways through chemical screening, and develop mouse models to explore the impact of blocking or stimulating PITT channels.

In summary, the study found that the PITT pathway is the core mechanism of the enzyme repair. In the PITT pathway, the start signal PI4P recruits ORP family protein to promote the strong interaction between the intravascular mesh and damaged iconic iconic body, and then activate cholesterol and PS to be transferred to the lyon. Large -scale lipid transportation directly repair the enzyme vulnerabilities.

Attachment: Dr. JAY XIAON TAN, the first and common communication authors, has established an independent laboratory at the Department of Cell Biology at the University of Pittsburgh Medical College, and is currently recruiting postdoctoral. Welcome students who are interested in visiting the laboratory website https://jaytanlab.org.

Original link:

https://www.nature.com/articleS/S41586-022-05164-4

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