Enzyme discovery offers new way to regulate cell death process for inflammatory diseases

A WEHI-led study has identified a new enzyme involved in controlling cell death, in findings that could lead to better treatment options for a range of inflammatory diseases, cancers and viruses.

This finding offers another way to regulate the cell death process for inflammatory diseases like psoriasis – conditions that occur due to excessive cell death in the body – and may also help reduce the severity of the disease in the future. viruses like COVID-19.

In one look

• Australian-Swiss research discovers a new way to control the process of cell death.
• Study reveals how an enzyme uses a ‘sugar mark’ to prevent excessive cell death.
• The findings could lead to better treatment options for infections, viruses and cancers of inflammatory origin.

Inflammatory cell death is an important part of the body’s immune response. But when left unchecked, it can lead to harmful amounts of inflammation in otherwise healthy organs and tissues, which fuels inflammatory diseases.

The WEHI-led collaboration, involving researchers from the University of Zürich, the University of Melbourne, the Hudson Institute for Medical Research and Monash University, discovered that an enzyme known as tankyrase -1 uses a “sugar tag” to prevent excessive cell death.

This finding could have implications for patients with chronic inflammatory diseases caused by unregulated cell death, such as psoriasis and rheumatoid arthritis.

It could also impact patients with inflammatory cancers, such as those of the intestine, where cell death is too low.

Posted in Scientists progressthe results could help improve treatment options for infections, chronic inflammatory diseases and certain cancers in the future.

The research was led by WEHI researchers Dr Lin Liu, Dr Najoua Lalaoui and Professor John Silke.

cursed temple

The new research focused on a protein called TNFR1, which exists on the surface of our cells and can induce a protein complex known to cause cell death.

Cells have many mechanisms to fight off pathogens, which viruses try to interfere with in order to stay alive. Our cells will trigger the TNFR1 death complex if they can detect pathogenic interference.

Professor John Silke compared it to a “temple of curse”.

Like how the ‘Doomed Temple’ tries to ensnare Indiana Jones, the Virus is the least lucky treasure hunter in this scenario.

Our cells have evolved to kill themselves when they detect a pathogen, to protect the body.

Since pathogens such as viruses need a living cell to replicate, the ‘doom temple’ created by our cells is a very effective way to stop a viral infection in its tracks.”

Professor John Silke, researcher, WEHI

Crucial sugar label

Lead author Dr Lin Liu said the team took advantage of mass spectrometry technology to identify the enzyme known as tankyrase-1 in the TNFR1 death complex.

“By isolating the TNFR1 cell death complex, we were able to show exactly how tankyrase-1 impacts cell death, in results that surprised us,” Dr. Liu said.

“While we have known for many years that tankyrase-1 plays a role in cell growth, our study is the first to link this enzyme to TNFR1-mediated inflammatory cell death.”

The researchers found that the enzyme plays a key role in clearing the TNFR1 death complex.

“We found that tankyrase-1 attaches sugar molecules called ribose to components of the TNFR1 death complex, which acts as a tag to trigger the elimination of the protein complex,” Dr. Liu said.

“This sugar tag is essential for clearing this complex and preventing excessive cell death.”

Improve therapeutic potential

Excessive virus-induced cell death has also been linked to disease severity.

Using a SARS-CoV-2 protein, the team was able to show how certain viruses can inadvertently trigger the death complex and the cell death process.

Dr Najoua Lalaoui said the findings could lead to ways to reduce the severity of certain viruses in the future.

“In healthy, uninfected cells, tankyrase-1 attaches the sugar group to the TNFR1 death complex to shut down its destructive capabilities,” she said.

“But during infections, the virus produces a protein that can remove the sugar group, which helps unlock the complex’s destructive potential.”

Tankyrase-1 is also known to play a role in certain cancers, with drugs that inhibit its function currently in preclinical trials.

Dr. Lalaoui said finding the enzyme’s role in cell death could lead to better treatment options for patients with certain inflammatory cancers.

“We suggest that anti-tankyrase drugs in the future could be specifically targeted at cancers that express TNF, as the drugs would then both stop cancer cell growth and trigger cell death to potentially make them more effective.

“Our findings lay the scientific groundwork that could lead to improved future treatments not only for certain cancers, but also for chronic inflammatory diseases.”

The research was supported by the NHMRC, the Victorian Government, the Australian Government, the Victoria Cancer Agency, the Independent Research Institutes Infrastructure Support Scheme, the Canton of Zurich and the Swiss National Science Foundation.