Scientists identify an enzyme that prevents excessive inflammatory cell death

Tankyrases protect against the cytotoxic effect of TNF under infection condition. Level of cytotoxicity assessed by LDH assay. iBMDMs were infected with S. Typhymurium SL1344 WT or ΔSPI-1 (MOI: 2) and treated with TNF (10 ng/ml) + Smac mimetic (250 nM; TS) ± IWR-1 (250 and 500 nM and 1, 2, and 5 μM) at 3 hpi. Cytotoxicity was then assessed by LDH assay of cell supernatants collected at 9 and 21 hpi. Graph shows means ± SEM. n = 3 independent experiments. Comparisons were performed between TS-treated uninfected and S. Typhimurium SL1344 WT or ΔSPI-1-infected cells at each IWR-1 concentration with a Student’s t test whose values are denoted as *P ≤ 0.05 and **P ≤ 0.01. Credit: Science Advances (2022). DOI: 10.1126/sciadv.abh2332

A study led by the WEHI has identified a new enzyme involved in regulating cell death; these findings could lead to improved treatments for a variety of inflammatory diseases, cancers, and viruses.

The discovery provides an additional method for regulating the cell death process in inflammatory diseases such as psoriasis and inflammatory bowel disease, which are caused by excessive cell death in the body, and may one day aid in reducing the severity of viruses such as COVID-19.

Inflammatory cell death is an essential component of the immune response of the body. But when unchecked, it can lead to harmful levels of inflammation in organs and tissues that are otherwise healthy, which fuels inflammatory disease.

Researchers from WEHI, Zürich University, the University of Melbourne, the Hudson Institute of Medical Research, and Monash University discovered that the enzyme tankyrase-1 uses a “sugar tag” to prevent excessive cell death.

This discovery may have implications for patients with chronic inflammatory diseases characterised by uncontrolled cell death, such as psoriasis and rheumatoid arthritis. It could also affect patients with inflammatory cancers, such as those of the colon, in which there is insufficient cell death.

The findings, which were published in Science Advances, could lead to improved treatment options for infections, chronic inflammatory diseases, and certain cancers in the future. The research was directed by Drs. Lin Liu, Najoua Lalaoui, and John Silke of the WEHI.

“Temple of disaster”

The focus of the new research was a protein called TNFR1 that exists on the surface of our cells and can induce a protein complex known to induce cell death.

Numerous mechanisms exist within cells to combat pathogens, which viruses attempt to interfere with in order to survive. If they detect pathogenic interference, our cells will activate the TNFR1 death complex.

This was described by Professor John Silke as a “temple of doom.”

In this scenario, the virus is the less fortunate treasure hunter, similar to how the Temple of Doom attempted to trap Indiana Jones. “To protect the body, our cells have evolved to the point where they will self-destruct upon detecting a pathogen. Since pathogens such as viruses require a living cell to replicate, the ‘temple of doom’ created by our cells is a highly effective method of preventing a virus infection.”

Important sugar label

Dr. Lin Liu, the study’s lead author, stated that the team utilised mass spectrometry to identify the enzyme known as tankyrase-1 within the TNFR1 death complex.

“By isolating the TNFR1 death complex from the cell, we were able to demonstrate exactly how tankyrase-1 influenced cell death,” Dr. Liu explained. Our study is the first to link tankyrase-1 to TNFR1-mediated inflammatory cell death; it has been known for many years that tankyrase-1 plays a role in cell growth.

Researchers discovered that the enzyme is essential for removing the TNFR1 death complex.

Dr. Liu explained, “We discovered that 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.” This sugar tag is necessary for removing the complex and preventing excessive cell death.

Increasing therapeutic viability

Virus-induced cell death in excess has also been linked to disease severity. Using a SARS-CoV-2 protein, the team was able to demonstrate that certain viruses can accidentally activate the death complex and cell death process. Dr. Najoua Lalaoui stated that the findings could lead to future methods for reducing the severity of certain viruses.

“In healthy, uninfected cells, tankyrase-1 attaches the sugar group to the TNFR1 death complex to inhibit its apoptotic properties,” she explained. “However, during an infection, the virus produces a protein capable of removing the sugar group, which helps unleash the complex’s lethal potential.”

Inhibitors of Tankyrase-1’s function are currently undergoing pre-clinical testing for the treatment of cancer.

Dr. Lalaoui stated that understanding the role of the enzyme in cell death could lead to improved treatment options for patients with certain inflammatory cancers. “We propose that in the future, anti-tankyrase drugs may be specifically targeted to cancers that express TNF, as the drugs would then both inhibit cancer cell growth and induce cell death, making them potentially more effective. Our findings are laying the scientific groundwork that may one day lead to improved treatments for chronic inflammatory conditions and certain types of cancer.”

Further information: Lin Liu et al, Tankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death, Science Advances (2022). DOI: 10.1126/sciadv.abh2332

Journal information: Science Advances

Source: Walter and Eliza Hall Institute of Medical Research