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open a little mouth

This is how you maintain a balanced diet of the autophagy organs - the self-eating mechanism in our body cells that removes waste and strengthens our health

Right: the opening (red) of the phagophore (green) remains narrow thanks to the coordinated activity of two protein clusters. Left: The opening widened after the scientists reduced the action of the valve that is responsible for closing it
Right: the opening (red) of the phagophore (green) remains narrow thanks to the coordinated activity of two protein clusters. Left: The opening widened after the scientists reduced the action of the valve that is responsible for closing it

Our body's cells clean themselves with the help of an intracellular waste removal process called "autophagy" - self-eating in Greek. However, as with any type of eating, autophagy should also be done in moderation. Recently, Weizmann Institute of Science scientists discovered a means of controlling this eating: the mechanism that maintains the size of the mouth of the organelle that performs the autophagy, and ensures that it opens exactly the right way and does not uncontrollably devour every component of the cells in its path. "The mechanism we discovered makes it possible to remove exactly the necessary amount of cellulosic waste, but no more than that," says Prof. Zebulon Elazar from the Department of Biomolecular Sciences who headed the research group.

Autophagy is mainly intended for the removal of large waste, such as damaged protein aggregates or organelle parts. In extreme situations, hunger for example, it can even break down cellular material randomly to provide building blocks for essential processes in the cell. Since autophagy is important for many body systems, and especially for the maintenance of long-lived cells that do not regenerate, including nerve cells, disturbances in the cleaning process can lead to a host of diseases; For example, failures in autophagy can lead to the death of nerve cells in Parkinson's disease and other degenerative brain diseases. In addition, the decrease in the extent of autophagy that occurs with age increases the risk of various diseases, including cancer.

In a new study in Prof. Elazar's laboratory, the scientists led by doctoral student Oren Shatz set out to find out how the body regulates the autophagy mechanism. Since the needs of the cell are constantly changing, the autophagy machines - organelles called autophagosomes - reassemble themselves each time and are destroyed when their work is finished. The structure from which the autophagosome develops has a double membrane known as a phagophore that can wrap the cellular material intended for disposal, similar to a garbage bag, and direct it to a "dump" - an organelle known as a lysosome - where it is broken down. There are phagophores that are able to swallow everything that comes their way in an unselective manner, while others are very selective - they use the proteins that "feed them with a spoon", that is, they are responsible for transporting the waste intended for evacuation into their mouths.

""The mechanism we discovered makes it possible to eliminate exactly the necessary amount of cellulose waste, but no more than that"

Until now, the prevailing opinion among scientists was that in both cases, the picky and the non-picky, the phagophore opens its large mouth and burrows into its body the waste that requires removal. But the findings of the new study, done in yeast cells, show that this is not a faithful description of the eating habits of the existing autophagosome. "We discovered a mechanism that controls the opening of the mouth in autophagy," says Shatz. "This control is especially essential in the case of non-selective autophagy that may lead to the engulfment of the entire cell from the inside."

The mechanism discovered in the study ensures that even in non-selective autophagy, the autophagosome will not fully open its jaws and devour everything that comes near. In fact, already in the process of creating the phagopore membrane, the size of the opening is determined and it does not change even when the membrane itself continues to grow and expand to contain the waste intended for removal. As a result, and contrary to the common perception, the phagophor is not similar in shape to a tea cup, but rather to a thin-necked pitcher, similar to the pottery known from ancient Greece. "Whatever the contents of the jar are, the opening will remain narrow," says Shatz. "In other words, it can be said that it was discovered that the autophagosome is not an all-devouring glutton, but a gourmet diner into which the chosen food gradually trickles through diffusion."

In the next step, the scientists showed that even in a selective autophagy scenario, the mouth of the phagophore does not open uncontrollably. In fact, even if the orifice that opens is larger than in the non-selective process, its size is regulated by the very same mechanism. At the end of the meal, the control mechanism is eliminated in both types of autophagy and allows the opening to close, the membrane to seal - and the ingested material to be digested.

Shatz and his colleagues also revealed the molecular details of this control mechanism: they showed that it includes two main protein clusters - one responsible for opening the mouth, and the other for closing it. After identifying the two components, the scientists showed with the help of innovative methods they developed that each of them can be controlled to increase or decrease the opening in a measured manner. The ability to adjust autophagy to the desired level and maintain a "balanced diet" may be a powerful tool in dealing with various diseases. "In cancer, for example, autophagy is a double-edged sword," explains Prof. Elazar. "Too little of it may lead to the accumulation of free radicals that are carcinogenic, but at the same time it itself is used by existing cancerous tumors and enables their survival."

Also participating in the study were Dr. Milena Freiberg, Damilula Isola, Dr. Shubhankar Das, Dr. Oli Gogoi and Dr. Alexandra Poliinsky from the Department of Biomolecular Sciences of the Institute, and the late Dr. Eyal Shimoni, Dr. Tali Dadosh, Dr. Neely Dzorla and Dr. Sharon Wolf from the Department of Chemical Research Infrastructures.

Our body's cells clean themselves with the help of an intracellular waste removal process called "autophagy" - self-eating in Greek. However, as with any type of eating, autophagy should also be done in moderation. Recently, Weizmann Institute of Science scientists discovered a means of controlling this eating: the mechanism that maintains the size of the mouth of the organelle that performs the autophagy, and ensures that it opens exactly the right way and does not uncontrollably devour every component of the cells in its path. "The mechanism we discovered makes it possible to remove exactly the necessary amount of cellulosic waste, but no more than that," says Prof. Zebulon Elazar from the Department of Biomolecular Sciences who headed the research group.

Autophagy is mainly intended for the removal of large waste, such as damaged protein aggregates or organelle parts. In extreme situations, hunger for example, it can even break down cellular material randomly to provide building blocks for essential processes in the cell. Since autophagy is important for many body systems, and especially for the maintenance of long-lived cells that do not regenerate, including nerve cells, disturbances in the cleaning process can lead to a host of diseases; For example, failures in autophagy can lead to the death of nerve cells in Parkinson's disease and other degenerative brain diseases. In addition, the decrease in the extent of autophagy that occurs with age increases the risk of various diseases, including cancer.

In a new study in Prof. Elazar's laboratory, the scientists led by doctoral student Oren Shatz set out to find out how the body regulates the autophagy mechanism. Since the needs of the cell are constantly changing, the autophagy machines - organelles called autophagosomes - reassemble themselves each time and are destroyed when their work is finished. The structure from which the autophagosome develops has a double membrane known as a phagophore that can wrap the cellular material intended for disposal, similar to a garbage bag, and direct it to a "dump" - an organelle known as a lysosome - where it is broken down. There are phagophores that are able to swallow everything that comes their way in an unselective manner, while others are very selective - they use the proteins that "feed them with a spoon", that is, they are responsible for transporting the waste intended for evacuation into their mouths.

""The mechanism we discovered makes it possible to eliminate exactly the necessary amount of cellulose waste, but no more than that"

Until now, the prevailing opinion among scientists was that in both cases, the picky and the non-picky, the phagophore opens its large mouth and burrows into its body the waste that requires removal. But the findings of the new study, done in yeast cells, show that this is not a faithful description of the eating habits of the existing autophagosome. "We discovered a mechanism that controls the opening of the mouth in autophagy," says Shatz. "This control is especially essential in the case of non-selective autophagy that may lead to the engulfment of the entire cell from the inside."

The mechanism discovered in the study ensures that even in non-selective autophagy, the autophagosome will not fully open its jaws and devour everything that comes near. In fact, already in the process of creating the phagopore membrane, the size of the opening is determined and it does not change even when the membrane itself continues to grow and expand to contain the waste intended for removal. As a result, and contrary to the common perception, the phagophor is not similar in shape to a tea cup, but rather to a thin-necked pitcher, similar to the pottery known from ancient Greece. "Whatever the contents of the jar are, the opening will remain narrow," says Shatz. "In other words, it can be said that it was discovered that the autophagosome is not an all-devouring glutton, but a gourmet diner into which the chosen food gradually trickles through diffusion."

In the next step, the scientists showed that even in a selective autophagy scenario, the mouth of the phagophore does not open uncontrollably. In fact, even if the orifice that opens is larger than in the non-selective process, its size is regulated by the very same mechanism. At the end of the meal, the control mechanism is eliminated in both types of autophagy and allows the opening to close, the membrane to seal - and the ingested material to be digested.

Shatz and his colleagues also revealed the molecular details of this control mechanism: they showed that it includes two main protein clusters - one responsible for opening the mouth, and the other for closing it. After identifying the two components, the scientists showed with the help of innovative methods they developed that each of them can be controlled to increase or decrease the opening in a measured manner. The ability to adjust autophagy to the desired level and maintain a "balanced diet" may be a powerful tool in dealing with various diseases. "In cancer, for example, autophagy is a double-edged sword," explains Prof. Elazar. "Too little of it may lead to the accumulation of free radicals that are carcinogenic, but at the same time it itself is used by existing cancerous tumors and enables their survival."

Also participating in the study were Dr. Milena Freiberg, Damilula Isola, Dr. Shubhankar Das, Dr. Oli Gogoi and Dr. Alexandra Poliinsky from the Department of Biomolecular Sciences of the Institute, and the late Dr. Eyal Shimoni, Dr. Tali Dadosh, Dr. Neely Dzorla and Dr. Sharon Wolf from the Department of Chemical Research Infrastructures.