London, March 1 : Researchers at St. Jude Children's Research Hospital have achieved a breakthrough understanding how certain proteins control the process of apoptosis, which rids the body of faulty or unneeded cells.
The researchers insist that understanding the fine points of apoptosis, also known as programmed cell death, is very significant for scientists who are working on ways to control this process.
A series of experiments carried out by the researchers demonstrated that certain cells would lose the ability to protect themselves from apoptosis in the absence of any one of three molecules.
"This is probably the first description of what is happening mechanistically that contributes to the ability of cells to delay apoptosis. It provides incredible insights into how three proteins work and how they can control apoptosis," Nature magazine quoted James Ihle, chair of the St. Jude Department of Biochemistry, as saying.
The researchers say that the molecular interactions discovered by them play out nerve cells and blood cells that develop from haematopoietic (blood-forming) stem cells.
A recent study had revealed that Kostmann's syndrome-a potentially fatal inherited deficiency of granulocytes in children which is caused by excessive apoptosis of granulocytes-results from a deficiency in one of the three proteins, called Hax1. "This suggests that the protein is playing basically the same role in humans as we described in mice," Ihle said.
St. Jude biochemists have long studied how cytokines-small proteins used by neurons and blood-borne cells to communicate messages-contribute to keeping cells alive. They had earlier shown that most cytokines controlling haematopoietic cells require an enzyme called Jak2, or Jak3 in lymphocytes, at the receptors where cytokines attached to the cell.
In screening for components that are regulated by the Jak enzymes, the St. Jude team found the Hax1 protein.
"That was intriguing because several studies suggested that Hax1 was controlled by cytokine signalling. Also, studies have suggested that if you overexpressed Hax1 in cells, the cells were protected from undergoing apoptosis," Ihle said.
During the study, the researchers genetically engineered mice to lacked the gene for Hax1, and found that apoptosis in the animals' brain caused extensive nerve cell degeneration that killed the mice within 10 to 12 weeks.
The study also revealed that apoptosis in immune-system lymphocytes occurred in the altered mice eight hours sooner than in those with the Hax1 gene, when limited amounts of cytokines were available.
"That additional window of survival is extremely important because in the body, cytokines are limiting. The key observation was that Hax1 was important in helping cells to survive. Importantly, what happened to the mice we generated was remarkably similar to what happens if you remove the mitochondrial enzymes called HtrA2 or Parl." Ihle said.
Exploring the similarities, the investigators found that Hax1 and Parl pair up in the inner membrane of the mitochondria-tiny chemical packets that serve as the main energy source for cells.
HtrA2 is made in the cell's cytoplasm and is transported into the mitochondria, where the enzyme must have a region removed for it to be active. This requires snipping away 133 amino acids, the building blocks of proteins.
The St. Jude researchers demonstrated that it is the Hax1/Parl pair that positions HtrA2 to allow the precise snipping that is required. Without Hax1, the snipping does not occur and HtrA2 remains inert.
Since members of the Bcl-2 family of proteins both protect and initiate apoptosis in lymphocytes, Ihle's team explored this family of proteins to understand why lymphocytes needed an active HtrA2 mitochondrial enzyme. They found that if active HtrA2 were present, the incorporation of a protein called Bax into the mitochondrial outer membrane did not occur.
This was significant since accumulation of Bax in the outer mitochondrial membrane allows the release of proteins that set off a chain of biochemical reactions, including the activation of enzymes that are responsible for cell death.