Pyroptosis is a series of biochemical reactions, which cause cell death. The process is long thought to be irreversible once initiated. But, a new study by the University of Illinois Chicago suggests that Pyroptosis can be halted and controlled.
In the study, scientists reported a new method for analyzing this process of cell death. In particular, they designed an “optogenetic” gasdermin by genetically engineering the protein to respond to light.
Gary Mo, UIC assistant professor in the department of pharmacology and regenerative medicine and the department of biomedical engineering at the College of Medicine, said, “The cell death process plays an important role in the body, in both healthy states and unhealthy ones, but studying pyroptosis — which is a major type of cell death — has been challenging.”
“Methods to examine the pyroptosis mechanisms at play in live cells are difficult to control because they are initiated by unpredictable pathogens, which in turn have disparate effects in different cells and people.”
“Our optogenetic gasdermin allowed us to skip over 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.”
This study offers a new way to study diseases related to malfunctioning cell death processes.
Using their newly developed method with florescent imaging technology, scientists could precisely activate gasdermin in cell experiments and observe the pores under various circumstances. They discovered that certain conditions, like specific concentrations of calcium ions, triggered the pores to close within only tens of seconds.
This automatic response to external circumstances offers evidence that Pyroptosis dynamically self-regulates.
Mo said, “This showed us that this form of cell death is not a one-way ticket. The process is programmed with a cancel button, an off-switch. Understanding how to control this process unlocks new avenues for drug discovery, and now we can find drugs that work for both sides — it allows us to think about tuning, either boosting or limiting, this type of cell death in diseases, where we could previously only remove this important process.”
- Santa Cruz Garcia, A.B., Schnur, K.P., Malik, A.B. et al. Gasdermin D pores are dynamically regulated by local phosphoinositide circuitry. Nat Commun 13, 52 (2022). DOI: 10.1038/s41467-021-27692-9