Scientists uncover new information about cellular death process,
previously thought to be irreversible
Study published in Nature Communications

Date:
January 10, 2022
Source:
University of Illinois Chicago
Summary:
Researchers report a new method for analyzing pyroptosis --
the process of cell death that is usually caused by infections
and results in excess inflammation in the body -- and show that
the process, long thought to be irreversible once initiated,
can in fact be halted and controlled. The discovery means that
scientists have a new way to study diseases that are related to
malfunctioning cell death processes and infections that can be
complicated by out-of-control inflammation.



FULL STORY ==========================================================================
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 excess inflammation in the body -- and shows that process, long thought to be irreversible once initiated, can in fact be halted and controlled.


==========================================================================
The discovery, which is reported in Nature Communications, means
that scientists have a new way to study diseases that are related to malfunctioning cell death processes, like some cancers, and infections
that can be complicated by out-of-control inflammation caused by
the process. These infections include sepsis, for example, and acute respiratory distress syndrome, which is among the major complications
of COVID-19 illness.

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

"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," 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 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," Mo said.

The researchers applied this tool and used florescent imaging technology
to precisely activate gasdermin in cell experiments and observe the pores
under various circumstances. They discovered that certain conditions,
like specific concentrations of calcium ions, for example, triggered
the pores to close within only tens of seconds.

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

"This showed us that this form of cell death is not a one-way ticket. The process is actually programmed with a cancel button, an off-switch,"
Mo said.

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

========================================================================== Story Source: Materials provided by University_of_Illinois_Chicago. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ana Beatriz Santa Cruz Garcia, Kevin P. Schnur, Asrar B. Malik,
Gary C.

H. Mo. Gasdermin D pores are dynamically regulated by local
phosphoinositide circuitry. Nature Communications, 2022; 13 (1)
DOI: 10.1038/s41467-021-27692-9 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220110184850.htm
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