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Research Provides New Insights Into ‘Infernal’ Mode of Cell Death

The body doesn’t mourn the loss of an infected or cancerous cell. Some cells die quietly, like a wounded animal searching for cover. Others go down in a blaze of publicity, poking holes in their membranes and spewing out substances that broadcast the news to the immune system. 

The latter mode of death — known as pyroptosis, from the Greek roots for “fire” and “falling” – serves a dual purpose. It does away with the infected cell, where a dangerous bacterium or virus has taken shelter, and it triggers an inflammatory response from the immune system, which traps the harmful germs and starts the healing process. 

A group of scientists at Dana-Farber have trained their attention on an ancient family of proteins, called gasdermins, that punch holes, or pores, in the cell membrane during pyroptosis. In a recent study in the journal Nature, they provide an atomic-level look at the structure of gasdermin pores from bacterial cells and offer a stepwise description of how they form. 


An artist’s depiction of gasdermin pores in bacterial cells, the subject of a new study by Dana-Farber scientists. Art by Evan Tear Haynes

The findings reveal the diversity of gasdermin pores found in nature, and hint at the multiple purposes such pores serve. They may even provide clues to a novel way of inducing cancer cells to kill themselves. 

Researchers began by engineering a panel of gasdermin proteins that were homologues – biochemical lookalikes — of gasdermins from a variety of bacteria types. The engineering allowed the researchers to make scores of gasdermin pores on demand. Then, using cryo-electron microscopy, in which biomolecules are flash frozen and then bombarded with electrons, they made detailed images of the pores. (The research was done in bacterial proteins to understand the evolutionary principles of gasdermin activation.) 

“We found that different gasdermins produce pores of distinct sizes, ranging from smaller ones, like those that form in mammalian cells, to exceptionally large ones,” says Dana-Farber’s Alex Johnson, PhD, who led the study with Philip Kranzusch, PhD. “Large” is a relative term: the average bacterial cell has a diameter of about one micron (a millionth of a meter); the biggest of the gasdermin pores is about one-twentieth of a micron. 

The variety of pore sizes came as something of a surprise, Johnson relates. “Bacterial cells are smaller than human cells, so I naively expected that the bacterial pores would be smaller than those from humans. We found the opposite to be the case.” Pores of different sizes may be needed to accommodate the different substances released during pyroptosis. 

Words like “poke” and “punch” may give the impression that the process of creating a bacterial pore is somewhat violent and haphazard. In fact, it’s the very essence of orderliness. It follows four steps in which an activated gasdermin protein targets a site on the membrane, implants itself there, joins with other bits of protein, and ultimately forms an opening lined with protein molecules – somewhat like a grommet sewn into a fabric.   

In some cases, the inner rim of the pore consists entirely of proteins arrayed picket fence-style. Previously, Johnson, Kranzusch and their colleagues had shown that the bacterial gasdermin molecule comes pre-stitched to a lipid compound called palmitoyl even before reaching the membrane to make a pore. In the new study, they report that palmitoyl inserts itself in the membrane before parts of the gasdermin proteins take their place there — clarifying a key step in pore formation. 

“The unique system enabled us to perform simulations that show how the attachment of lipids allows the gigantic gasdermin pores to form in the membrane,” Johnson says. 

The finding that bacterial cells can develop pores of different sizes sets the stage for research into the different substances that pour from the pores during pyroptosis. “Are they involved in cell-cell communication among bacteria, or do they have some other role in nature?” Johnson asks. “We also want to explore how human cells evolved these pores for releasing cytokines,” signaling molecules that provoke an immune system response. “The recent work from our group and others in the field opens the door for studying cell death processes in unicellular organisms to better understand how such processes work in human cells.”