Science Advances: Do not break or stand?

The cytoplasmic membrane is an extremely thin membrane that surrounds the surface of the cell and is also the "protective umbrella" for its survival and development
.

Even if it is “arrogant” such as cancer cells, damage to the plasma membrane can have devastating effects

Recently, researchers from the Danish Cancer Society Research Center, the University of Copenhagen, and the University of Southern Denmark published a research report titled Restructuring of the plasma membrane upon damage by LC3-associated macropinocytosis in Science Advances , stating that cancer cells can pass through large cells.
Macropinocytosis, which "eats" the damaged area of ​​cells so as to survive a critical juncture .
It is worth noting that the researchers also discovered a unique membrane reorganization mechanism, which laid the foundation for people to inhibit the spread of cancer cells and eliminate tumors .

Science Advances Restructuring of the plasma membrane upon damage by LC3-associated macropinocytosis

Before entering the topic, we need to introduce the autophagy and large-scale pinocytosis related to cell damage and repair
.

Autophagy is a recycling system that is ubiquitous in most eukaryotic cells.
It can be like a "garbage treatment plant" that converts damaged structures in cells into nutrients for recycling

Previous studies have shown that the repair mechanism of the cell plasma membrane relies on biological processes such as endocytosis, exocytosis, and membrane shedding mechanisms.

Annexin can promote the fusion of the plasma membrane around the damaged part of the cell through a series of reactions, thereby temporarily preventing the intracellular Outflow of liquid

In order to uncover the mechanism behind cell repair, the researchers used ablation lasers to damage human breast cancer cells MCF7 cells and cervical cancer cells HeLa cells, and found that the cells can be closed again within 20-30 seconds, and surprisingly, Cell damage will cause membrane folds, and two protein vesicles related to autophagy are formed in this area: one is Rab5-positive large vesicles that originate from the damaged area of ​​the plasma membrane and are associated with early endocytosis.
The plasma membrane begins to form about 2-5 minutes after injury; the other is the expression of microtubule-associated protein 1 light chain 3 (LC3, a protein related to autophagy) positive vesicles that appear in the repair area, which are damaged in cells 8 Formed at ~10 minutes
.

Over time, the two vesicles will eventually co-localize in the cell repair area and appear to fuse

LC3 vesicles after plasma membrane damage

LC3 vesicles after plasma membrane damage LC3 vesicles after plasma membrane damage

Rab5 large vesicles appearing at the damaged plasma membrane and co-localization of the two vesicles

Rab5 large vesicles appearing at the damaged plasma membrane and co-localization of two vesicles Rab5 large vesicles appearing at the damaged plasma membrane and co-localization of two vesicles

What kind of "mission" does these vesicles formed after the plasma membrane are damaged? To explore this question, the researchers used confocal time-lapse imaging to track the fate of Rab5 large vesicles filled with extracellular fluid.
Observations showed that these vesicles contract spontaneously later, and this contraction seems to be affected by the vesicles.
Driven by the removal of liquid in the bubble
.

In addition, LC3-positive vesicles then appear to fuse with lysosomes and be further internalized through the lysosomal degradation system

The above situation shows that cell repair seems to be inseparable from large-scale pinocytosis
.

In order to verify this, the researchers used relevant inhibitors to treat the relevant cells.

In short, the cells damaged by the ablation laser can pull the intact cell membrane into the damaged area, thereby sealing the cells within a few minutes
.

Subsequently, the cell will transport the damaged area in the form of vesicles to the inside of the cell through large pinocytosis for "recycling".

It is worth noting that in this new study, the researchers also discovered that the plasma membrane repair process is achieved by triggering a previously unknown atypical autophagy process
.

Normally, autophagy is initiated by the ULK1/ATG13/WIPI2 pathway, but the cells in this study "do not take the usual path", and this process is highly dependent on rubicon protein, atypical autophagy-LC3-related autophagy (LAP) Similarly, researchers call this newly discovered atypical autophagy process as LC3-related large pinocytosis (LAM)

More than just helping damaged cells to recover, an article in Nature Communications in 2020 pointed out that large-scale pinocytosis is also an important cause of tumor resistance, and blocking this process can restore cancer cells' sensitivity to drugs
.

In short, this study shows that cells can trigger giant pinocytosis to "cure injuries" after being damaged
.
The corresponding author of the report, Stine Lauritzen S of the Danish Cancer Society Research Center? Nder said: "We believe that the process of cancer cell recovery through macropinocytosis after plasma membrane damage may not be the end point.
This may be just an emergency measure.
Afterwards, the cancer cells may undergo more thorough repairs, which may help us.
To discover another weakness of cancer cells, we will continue to explore
.
"

Original source:

Original source:

Stine Lauritzen Snder, et al.
Restructuring of the plasma membrane upon damage by LC3-associated macropinocytosis.
Science Advances, 02 Jul 2021: Vol.
7, no.
27, eabg1969.
DOI: 10.
1126/sciadv.
abg1969.

Restructuring of the plasma membrane upon damage by LC3-associated macropinocytosis.
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