Newly Identified Aspect of Cell Death May Impact Future of Fighting Diseases

Without Caspase-7-NR
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Edward Miao, PhD

Enabling or inhibiting a certain enzyme could trigger the body’s natural immune response

Researchers have unmasked a component of the cell death process that could play a vital role in a better infection-fighting strategy.

Scientists at the Duke University School of Medicine partnered with the University of North Carolina at Chapel Hill and the University of Virginia to identify the function behind caspase-7, an enzyme that is part of a cell’s self-destruct program. While researchers have known the enzyme is involved in the process, its exact function has been unclear.

The findings are published June 15 in the journal Nature.

The researchers found that caspase-7 kicks off a Rube Goldberg series of events that allow the cell to die in an orderly fashion, said the study’s corresponding author, Edward Miao, M.D., Ph.D.,a professor in the departments of Immunology and Molecular Genetics and Microbiology at the Duke University School of Medicine.

An orderly cell death is essential for the immune response. Without the enzyme, however, the dying cell might violently explode and cause collateral damage.

Miao said this research lays groundwork to explore exciting possibilities for therapeutic applications, especially if caspase-7 can be boosted or blocked.

“There is still so much we need to understand about the basic components of our cells, what they do and why,” Miao said. “If we can uncover this blueprint, it may become a map for understanding how disease moves in the body, allowing scientists to devise a more precise plan of action. With the discovery of caspase-7’s role in the cell, we’re one step closer to a complete schematic.”

In the study, the researchers found that caspase-7 serves as a timing device in cell death. It activates a protein, called acid sphingomyelinase or ASM, which kicks off a cell membrane repair mechanism, which in turn gives the cell enough time to get its affairs in order before dying.

To identify the function of the caspase-7 enzyme, the team studied different infection models in genetically altered mice and cultured intestinal tissue. They looked at caspase-7’s role in two types of orderly cell death -- extrusion and apoptosis.

Caspase-7’s role was different in the context of different pathogens – Salmonella, Listeria and a rare pathogen called Chromobacterium.

With Salmonella, cells undergo an orderly manner of cell death called extrusion. In this context, researchers found the absence of caspase-7 caused the unnecessary death of healthy cells, which were the collateral damage of nearby infected cells failing to detach themselves, or extrude, from their neighbors.

With Chromobacterium and Listeria, dying cells normally undergo a process called apoptosis, or programmed cell death. The lack of caspase-7 enabled the bacteria to survive an immune system attack, presumably because their infected cell host didn’t accomplish some apoptotic task before exploding.

If caspase-7 can be manipulated, Miao said a potential application is investigating the possibility of targeting the enzyme as a detonator of cell death to circumvent antibiotic resistance.

Antibiotics are a standard and broad approach for fighting infection, but pathogens have devised strategies to adapt and resist.

“Antibiotics don’t take into account that each pathogen has its own strategy -- some of them are living outside cells, some are living inside cells. If a pathogen is inside the cell,” he said, “you could boost caspase-7 to allow the infected cell to die in the correct way. If you know the strategy that the pathogen is using, you can help the immune system by tweaking it in the correct direction.”

“On the other hand, if you have a pathogen traveling outside of the cell, and cells are exploding inappropriately, maybe we could boost caspase-7 to keep them alive, thereby prevent excessive damage,” Miao said, noting that this approach might be effective against sepsis. 

Miao said this enzyme could also potentially play a major role in triggering the immune system to fight cancer.

“Cancer cells are probably running the full Rube Goldberg machine and dying in an orderly manner,” Miao said. “When the immune system comes and looks around, it sees that everything seems to be in order and then leaves.

“If you could shut down the Rube Goldberg contraption, instead of putting itself away nice and neat, the tumor cell would be just dead on the floor,” Miao said. “This might cause the immune system to become alarmed and activated. Theoretically, that could cause the immune system to attack a tumor it would otherwise ignore.”

In addition to Miao, study authors include Kengo Nozaki, Vivien I. Maltez, Manira Rayamajhi, Alan L. Tubbs, Joseph E. Mitchell, Carolyn A. Lacey, Carissa K. Harvest, Lupeng Li, William T. Nash, Heather N. Larson, Benjamin D. McGlaughon, Nathaniel J. Moorman, Michael G. Brown, and Jason K. Whitmire.

The study was funded by the National Institutes of Health (AI097518, AI133236, AI139304, AI119073, AI136920, AI097518-02S1, AI110682 and AI074862, AI050072.)

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