By Nick Lavars May 16, 2022
A new discovery around excessive cell death in the body offers new hope of treating conditions driven by chronic inflammation Depositphotos
Uncontrolled inflammation in the human body can drive a variety of serious health conditions, including cancer and rheumatoid arthritis, so discoveries around how it works can benefit the field of medicine in wide-ranging ways. A new example of this illuminates the key role a certain enzyme plays in the process, and how it uses a type of “sugar tag” to prevent excessive death of healthy cells.
Led by scientists at the Walter and Eliza Hall Institute of Medical Research, the study sought to zero in on inflammatory disease, a root cause of excessive cell death. One form of this is an over-extension of a natural defense mechanism used by our cells when they encounter pathogens, which is to activate a protein complex called TNFR1.
Referencing the popular Indiana Jones film franchise, the scientists liken this to a “temple of doom,” in the sense that TNFR1 essentially traps the pathogen as it seeks to interact with cells in order to survive and thrive.
“Like how the ‘temple of doom’ tries to trap Indiana Jones, the virus is the less fortunate treasure hunter in this scenario,” said study author John Silke. “Our cells have evolved to the point where they will kill themselves when they detect a pathogen, to protect the body. Since pathogens such as viruses need a living cell to replicate in, the ‘temple of doom’ created by our cells is a very effective way to stop a virus infection in its tracks.”
To learn more about this process, the authors used mass spectrometry to watch this “temple of doom” at work in precise detail. This revealed an enzyme called tankyrase-1 stepping in to play an important role, in the sense that it actually prompts the removal of the TNFR1 death complex.
“We found tankyrase-1 attaches sugar molecules called ribose to components of the TNFR1 death complex, which acts as a tag to trigger the removal of the protein complex,” said study author Dr Lin Liu. “This sugar tag is essential to removing this complex and preventing excessive cell death.”
The possibility of targeting this sugar tag mechanism to manipulate excessive cell death could lead to new treatments for a range of conditions driven by chronic inflammation, such as inflammatory bowel disease and psoriasis, to name just a couple. It could also create new opportunities to treat cancers driven by inflammation, where anti-tankyrase drugs could be used to target cancerous cells expressing the TNFR1 death complex, leaving them to more readily die off.
Another possibility is in tempering the severity of viruses. In one experiment, the team demonstrated how a SARS-CoV-2 protein essentially neutralizes the sugar tag, activating the death complex and initiating the excess cell death process. Finding ways to intervene in this process could result in effective new treatments for viruses like SARS-CoV-2.
“By isolating the TNFR1 death complex from the cell, we were able to show exactly how tankyrase-1 impacted cell death, in findings that took us by surprise,” Liu said. While we’ve known for many years that tankyrase-1 plays a role in fueling cell growth, our study is the first to link this enzyme to TNFR1-mediated inflammatory cell death.”
The research was published in the journal Science Advances.
Source: Walter and Eliza Hall Institute of Medical Research
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