The gallows, the guillotine, and the gas chamber inspire a special dread because, unlike human executioners, they are machines. Such machines have even been described as monsters that live awful lives born of the death they deal. At the cellular level, however, execution machines are accompanied by stay-of-execution machines, which may even act as rescue machines, should they stall programs of death long enough for cells to repair damage or fight infection.
A stay-of-execution machine called ESCRT-III has recently been reexamined by a team of St. Jude Children’s Research Hospital scientists. ESCRT-III, which is one of several ESCRT (endosomal sorting complex required for transport) complexes, has long been known to participate in membrane abscission and viral budding. In addition, reports the St. Jude team, ESCRT-III can delay or prevent necroptosis, a form of programmed inflammatory cell death.
Details of the new study appeared April 6 in the journal Cell, in an article entitled, “ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences.” MLKL, or mixed lineage kinase-like, is the “business end” of the necroptosis machinery. Specifically, when MLKL is activated by this machinery, it triggers a piercing of the plasma membrane surrounding the cell, ultimately killing it. However, the St. Jude scientists discovered that the cell’s plasma membrane can repair itself by forming “bubbles” of broken plasma membrane. These bits of membrane are shed by the cell, which then repairs the holes.
“The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed,” wrote the authors of the Cell article. “Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.”
The investigators emphasized that activating MLKL is not a point of no return for cell survival, and that ESCRT-III can resuscitate damaged cells.
In experiments relevant to transplantation, the researchers measured levels of activated MLKL protein in tissue samples from kidneys used in transplants. Such cells experience stress during the transplantations, and researchers suspected the cells would show signs of necroptosis. The scientists found that although MLKL was activated in the kidney cells after transplantation, the cells did not die, and this protection correlated with an increase in the levels of the ESCRT-III machinery necessary for rescue of cells with active MLKL.
Senior author Douglas R. Green, Ph.D., emphasized that the current findings are only “suggestive” at this point, because the experiments were done in cell cultures and tissue samples. Further studies are needed to establish that the rescue machinery functions in whole organs. For example, the researchers are working with clinicians to explore whether ESCRT-III could aid transplant survival.
The research by Green and his colleagues will also aim at discovering the biological signals regulating ESCRT-III to enable more precise control of the rescue machinery. Those studies could yield drugs to regulate the rescue process, Green said.
Rescue treatments that prevent necroptosis in transplanted organs could reduce injury to the transplant caused by lack of oxygen, researchers said. Drugs to rescue cells from necroptosis could also help prevent injuries to tissue deprived of blood by heart attack and stroke. In such cases, restoring blood flow and oxygenation triggers inflammation that kills tissue.
The researchers said cell-rescuing drugs could also thwart cancer spread by protecting blood vessel cells from being killed by tumor cells. Tumor cells escape the bloodstream to spread in the body by killing blood vessels. Blocking the rescue machinery might also prove useful in treating cancers by enhancing death of cancer cells by necroptosis.
In treating neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS)—also known as Lou Gehrig's Disease—activating the rescue machinery could help prevent death of brain cells.
And in treating viral infections such as influenza, rescue treatment could extend the life of cells infected by the virus, so that the body's immune system would be more strongly alerted to fight the infection.
The Green laboratory has a long history of pioneering research into the two forms of cell death—apoptosis and necroptosis. In 1995, Green and his colleagues discovered a hallmark event characteristic of apoptosis—the movement of a fatty molecule called phosphatidylserine from the inside of the plasma membrane to the outside. This study established phosphatidylserine movement as a hallmark of necroptosis.