Scientists discover how to stop and control cellular death process – previously thought to be irreversible

Cell and Pyroptose

A composite image of a cell through pyroptosis. Credit: Gary Mo.

A study published by researchers at the University of Illinois Chicago describes a new method for analyzing pyroptosis – the process of cell death that is usually caused by infections and results in excessive inflammation in the body – and shows the process that has long been considered irreversible once initiated, can actually be stopped and controlled.

The discovery, which is reported in Nature Communications, means that researchers have a new way of studying diseases related to malfunctions in cell death processes, such as some cancers, and infections that can be complicated by out of control inflammation caused by the process. These infections include e.g. sepsis and acute respiratory distress syndrome, which are among the major complications of COVID-19 disease.

Pyroptosis is a series of biochemical reactions that use gas dermin, a protein, to open large pores in the cell membrane and destabilize the cell. To understand more about this process, UIC researchers designed an “optogenetic” gas termine by genetically engineering the protein to respond to light.

“The cell death process plays an important role in the body, both in healthy and unhealthy conditions, but studying pyroptosis – which is a major type of cell death – has been challenging,” said Gary Mo, UIC assistant professor in the Department of Pharmacology and Regenerative Medicine and the Department of biomedical engineering at the College of Medicine.

Mo said that methods to study the pyroptosis mechanisms at play in living cells are difficult to control because they are initiated by unpredictable pathogens, which in turn have different effects in different cells and humans.

“Our optogenetic gas termine allowed us to skip the unpredictable pathogen behavior and the variable cellular response because it mimics at the molecular level what happens in the cell once pyroptosis is initiated,” said Mo.

The researchers used this tool and used fluorescent imaging technology to accurately activate gas termine in cell experiments and observe the pores under different circumstances. They discovered that certain conditions, such as specific concentrations of calcium ions, for example, caused the pores to close in just ten seconds.

This automatic response to external circumstances provides evidence that pyroptosis dynamically self-regulates.

“This showed us that this kind of cell death is not a single ticket. The process is actually programmed with a cancel button, an off-switch,” said Mo. “Understanding how to control this process opens new avenues for drug discovery, and now “we can find drugs that work for both sides – it allows us to think about adjusting, either boosting or limiting, this type of cell death in diseases where we could previously only eliminate this important process.”

Reference: “Gasdermin D Pores Dynamically Regulated by Local Phosphoinositide Circuits” by Ana Beatriz Santa Cruz Garcia, Kevin P. Schnur, Asrar B. Malik, & Gary CH Mo, January 10, 2022, Nature communication.
DOI: 10.1038 / s41467-021-27692-9

Co-authors of the Nature Communications paper, “Gasdermin D Pores Are Dynamically Regulated by Local Phosphoinositide Circuitry,” are Ana Santa Cruz Garcia, Kevin Schnur, and Asrar Malik, all from UIC.

The research was funded by grants from the National Institutes of Health (P01HL060678, R01HL090152, R01HL152515, T32HL007820, P01HL151327).

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