How do we kill rogue cells? Assassin's tricks revealed

October 31, 2010
How do we kill rogue cells? Assassin's tricks revealed
Model of a membrane with perforin rings allowing the passage of granzymes into the cell. Credit: Mike Kuiper

A team of Melbourne and London researchers have shown how a protein called perforin punches holes in, and kills, rogue cells in our bodies. Their discovery of the mechanism of this assassin is published today in the science journal Nature.

"Perforin is our body's weapon of cleansing and death," says project leader Prof James Whisstock from Monash University.

"It breaks into cells that have been hijacked by viruses or turned into and allows toxic enzymes in, to destroy the cell from within. Without it our immune system can't destroy these cells. Now we know how it works, we can start to fine tune it to fight cancer, malaria and diabetes," he says.

The first observations that the human immune system could punch holes in target cells was made by the Nobel laureate Jules Bordet over 110 years ago. But how?

Researchers from Monash University and the Peter MacCallum Cancer Centre in Melbourne, and Birkbeck College in London collaborated on the ten-year study to unravel the and function of perforin—the protein responsible. The structure was revealed with the help of the Australian Synchrotron, and with powerful electron microscopes at Birkbeck. Combining the detailed structure of a single perforin molecule with the electron microscopy reconstruction of a ring of perforins forming a hole in a model membrane reveals how this protein assembles to punch holes in cell membranes.

The new research has confirmed that the important parts of the perforin molecule are quite similar to those in toxins deployed by bacteria such as anthrax, listeria and streptococcus. "The molecular structure has survived for close to two billion years, we think," says Prof Joe Trapani, head of the Cancer Immunology Program at Peter Mac.

"This work is a dramatic illustration of the importance of the synchrotron," says Whisstock. "We simply couldn't have done it without this wonderful facility."

The weapon of death is a powerful molecule. If perforin isn't working properly the body can't fight infected cells. And there is evidence from mouse studies, says Trapani, that defective perforin leads to an upsurge in malignancy, particularly leukaemia.

Perforin is also the culprit when the wrong are marked for elimination, either in autoimmune disease conditions, such as early onset diabetes, or in tissue rejection following bone marrow transplantation.

So the researchers are now investigating ways to boost perforin for more effective cancer protection and therapy for acute diseases such as cerebral . And with the help of a $1 million grant from the Wellcome Trust they are working on potential inhibitors to suppress perforin and counter tissue rejection.

More information: Law R et al. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 2010.

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1 / 5 (20) Oct 31, 2010
Perforin perforates cellular membranes destroying the affected cell. A cell is malfunctioning when the functioning instructions (DNA) are mutated. A mutation is a mistake in structuring.

Perforin is a molecule responsible for reading cells. By locating irregularities the mutation is singled out. At this point the molecule perforates the cell compromising its integrity, in effect, destroying it.

Could Perforin be the name of a specialized action undertaken by immune cells. After singling out the affected cell, the immune cell shoots out a perforating molecule to destroy the cell membrane killing the cell.

Interesting research.
1 / 5 (19) Oct 31, 2010
FYI: white cells or immune cells ARE stemcells. Stemcells are present in everyone, the number of stemcells lowers with aging.

Stemcells are the smartest of cells as they are the least specialized, they have the ability to undertake any cellular function.

Immune cells need the ability to recognize differences between cells. A specialized immune cell is dangerous, it finds all cells to be rogue but one. So if the immune cell is specialized to skin cells it will destroy muscle cells, bone cells etc. This is an auto immune disorder, specialized immune cells.

White cells that destroy tissue because they are misinterpreting the information as false are what is classified as an auto immune disorder.
not rated yet Oct 31, 2010
Regarding your first post and in particular, your 3rd paragraph-

Obviously not. Perforin is the name of the protein, not the signaling pathway. Why would there be discrepancy over the name of the protein? Why would you even ask that? I've been told there is no such thing as a stupid question, but you just asked a stupid question.
not rated yet Nov 01, 2010
but his question was not stupid until you said so. is it better not to ask a question or to ask a question that is thought to be stupid by someone who thinks he has above average intelligence that qualifies him to judge the nature of a question?
1 / 5 (19) Nov 01, 2010

"Could Perforin be the name of a specialized action undertaken by immune cells", I intended this to be a segway, focus shift from Perforin to immune cells. Maybe it came across as faulty, hey, you can be an immune cell of "Physorg", your words just perforated my comment bubble destroying the contents within. Are you sure you didn't single out the wrong cell to destroy? A bad immune cell can wreak havoc on the system ;)
not rated yet Nov 02, 2010
I think what he was saying what it is dangerous when you have an immune cell that is too specific for the place that it is. eg when there are immune cells that are in the brain (blood/brain barrier very impermeable)or an immune cell commonly found in the skin that gets inside one of your organism and having penetrated the organ, starts destroying things. There are two different types of immune responses. The neutrophil response where they just destroy unrecognised things and the targeted suicide type cells which look around for a specific protein target and when they find it they explode, releasing a noxious mixture and destroy everything in the vicinity. Those are two completely different parts of the immune system. The body has to manufacture the factories to build them to respond.Neutrophills are more of a police type response,whereas the latter are more specific, avoiding collateral damage. So a lot of times those codings would protect the infectious agents from damage also disguis

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